Biomedical subjects

H Golding

Publications and source records attributed to H Golding.

At least 55 records · Page 3Linked to original sources

PubMed1992

Correlation between kinetics of soluble CD4 interactions with HIV-1-Env-expressing cells and inhibition of syncytia formation: implications for mechanisms of cell fusion and therapy for AIDS.

OBJECTIVES: To study the kinetics of the interactions between soluble (s) CD4 and HIV-1-Env-expressing cells in relation to subsequent events leading to cell fusion and inhibition of syncytia formation. DESIGN: Vaccinia-HIV-1 (Env)-infected CD4- T-cells were used to study the kinetics of sCD4-gp120/41 interactions and syncytia formation (with CD4+ T-cells) under identical conditions. METHODS: sCD4 association and dissociation rates for HIV-1-Env-expressing cells, and quantification of sCD4-induced gp120 shedding was determined by a quantitative flow cytometry assay. Syncytia inhibition was measured in the continuous presence of sCD4, or after washing of HIV-1-Env-expressing cells following pre-incubation with sCD4. RESULTS: The kinetics of syncytia inhibition correlated with sCD4 binding when sCD4 was maintained during the culture. When Env-expressing cells, which had been pre-incubated with sCD4, were washed to remove unbound sCD4, no syncytia formation inhibition was observed, even following sCD4-induced shedding of greater than 50% of surface gp120 molecules. CONCLUSIONS: The lack of syncytia inhibition seen after removal of unbound sCD4, even after pre-incubation of cells under saturation and gp120 shedding conditions, indicated that sufficient numbers of fusogenic molecules remained on the sCD4-treated cells. In addition, fast dissociation of pre-bound sCD4 occurred in culture. These results are important for understanding HIV-1-Env-mediated cell fusion and AIDS therapy.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Kinetics of soluble CD4 binding to cells expressing human immunodeficiency virus type 1 envelope glycoprotein.

The high-affinity interaction between the envelope glycoprotein (gp120-gp41) of the human immunodeficiency virus type 1 and its receptor, CD4, is important for viral entry into cells and therapeutical approaches based on the soluble form of CD4 (sCD4). Using flow cytometry, we studied the kinetics of binding of sCD4 to gp120-gp41 expressed on the cell surface. sCD4 binding was dependent on sCD4 concentration and temperature and exhibited bimolecular reaction kinetics. Binding was very slow at low sCD4 concentrations (below 0.2 micrograms/ml) and low temperatures (below 13 degrees C) but increased sharply with increasing temperature. The rate constant for association at 37 degrees C (1.5 x 10(5) M-1 s-1) was 14-fold higher than at 4 degrees C, but the affinity of sCD4 to membrane-bound gp120-gp41 was not significantly affected. The activation energy at higher temperatures (28 to 37 degrees C) was less than at lower temperatures (4 to 13 degrees C). After long periods of incubation, we observed a decrease of surface-bound sCD4 and gp120, even at low temperatures, which was attributed to sCD4-induced shedding of gp120. The rate of gp120 shedding was much lower than the rate of sCD4 binding and was dependent on sCD4 concentration and temperature. The finding that sCD4 binding is slow, especially at low sCD4 concentrations, can be of critical importance for efficient blocking of viral infection by sCD4 and should be considered when designing new protocols in the therapy of AIDS patients.

CD4 Antigens↗

PubMed1992

Interactions of CD4+ plasma membrane vesicles with HIV-1 and HIV-1 envelope glycoprotein-expressing cells.

To study interactions between the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120-gp41) and the receptor in the target membrane, CD4, a new experimental system utilizing CD4-carrying plasma membrane vesicles (CD4 PMVs) was developed. CD4 PMVs were prepared by hypotonic lysis of HeLa cells expressing CD4 after infection with recombinant vaccinia virus containing the CD4 cDNA. The CD4 PMVs carried up to 680 CD4 molecules per vesicle. Their fusion with cells expressing gp120-gp41 after infection with recombinant vaccinia virus was monitored by fluorescence video microscopy by using lipophilic fluorescent dyes. Fluorescence changes as a result of fusion occurred within 30 min at 37 degrees C, and little fluorescence changes were seen with cells expressing the noncleaved HIV-1 envelope glycoprotein (gp160). The preincubation of CD4 PMVs with HIV-1 reduced its infectivity 10-fold. The CD4 PMVs were more effective in inhibiting syncytia formation than sCD4. These results demonstrate that CD4 PMVs could be used to study the mechanisms of HIV-1 envelope-mediated fusion and have the potential to inactivate HIV-1.

Animals↗

PubMed1991

A polymer containing a repeating peptide sequence can stimulate T-cell-independent IgG antibody production in vivo.

The immunogenicity of a CD4 peptide sequence 303-315 (V4 domain) was determined for three forms of the peptide: (a) a polymer consisting of repeating peptide units, (b) a peptide linked to a large protein carrier, chicken serum albumin, and (c) unmodified free peptide. Two in vivo systems were used: a T-cell-competent BALB/c mouse and a T-cell-deficient nude mouse. In BALB/c mice the IgG antibody responses to the peptide-CSA conjugate were at least 100-fold greater than the response to the polymer, and the free peptide gave no response. However, in contrast to the normal BALB/c mice, in the nude mice the polymer produced the only significant response. Nude mice immunized with the polymer produced a predominantly IgG response with almost equal amounts of IgG1 and IgG 2a + 2b. This IgG subclass distribution was very similar to that obtained in the BALB/c for the peptide-CSA conjugate. Positive sera from both groups were able to react with immobilized CD4 molecule on Western blots, confirming the specificity of both the T-cell-independent as well as T-cell-dependent response. These results suggest that repeating epitopes on the same peptide polymer molecule may cause cross-linking of antigen-specific immunoglobin receptors on B-cells, and thus behave as a relatively T-cell-independent immunogen which can induce isotype switching.

Amino Acid Sequence↗

PubMed1991

Common sequence in HIV 1 GP41 and HLA class II beta chains can generate crossreactive autoantibodies with immunosuppressive potential early in the course of HIV 1 infection.

We have previously reported the identification of highly conserved homologous regions located in the carboxy terminus of the HIV 1 gp41 (aa 837-844), and the amino-terminal of the beta chain of all human HLA class II antigens (aa 19-25). Murine monoclonal antibodies raised against synthetic peptides from these homologous regions bound not only to the isolated peptides, but also to "native" HLA class II molecules on cells. Screening of sera from HIV 1 infected individuals revealed high frequency of sera (35%) containing anti-class II crossreactive antibodies (CRAb), not only in AIDS patients, but also in early, asymptomatic patients. The CRAb containing sera caused potent inhibition of normal CD4-bearing cells' proliferative responses to tetanus toxoid in vitro. They could also kill class II bearing cells by ADCC. The possible contribution of these antibodies to the establishment of immunodeficiency state in HIV 1 infected individuals and/or to disease progression, was examined in two clinical studies: I. Asymptomatic patients were tested in parallel for their PBL responses to flu/tetanus, HLA alloantigens, and PHA (proliferation and IL2 production), and for the presence of anti-class II CRAb. About 50% of these patients showed a selective loss of their in vitro responses to recall antigens (flu/tetanus), which depend on CD4+ cells, while still responding to PHA and ALLO. Interestingly, positive correlation was found (P less than 0.001) between patients' lack of responsiveness to flu/tetanus and the presence in their sera of anti-class II CRAb. II. Retrospective study of HIV 1-infected hemophiliacs, suggest that patients with high titers of CRAb early in the disease progressed faster to full blown disease.

Amino Acid Sequence↗

PubMed1991

Production of a novel antigen by conjugation of HIV-1 to Brucella abortus: studies of immunogenicity, isotype analysis, T-cell dependency, and syncytia inhibition.

In the present study inactivated human immunodeficiency virus type 1 (HIV-1) was conjugated to Brucella abortus and tested for immunogenicity in normal and anti-L3T4-treated BALB/c mice. HIV-BA was more immunogenic than uncoupled HIV in normal mice, since 6-fold less virus in HIV-BA preparations elicited higher titer responses than HIV-1 alone. Furthermore, the HIV-BA antibody response reached higher levels before the HIV-1 response. Immunoblot analysis showed that most of the HIV-1 antigens were recognized by antibodies induced by either HIV-1 or HIV-BA. Isotype analysis revealed that HIV-1 induced similar levels of IgG1 and IgG2a antibodies, whereas the IgG2a responses to HIV-BA were more pronounced than the IgG1 response. These different IgG subclass patterns suggest that conjugation of HIV-1 to BA changed the immunogenic nature of HIV-1. The requirement for helper T cells was examined by immunizing mice that were depleted of CD4+ T cells by in vivo anti-L3T4 treatment. Under these conditions the IgG responses to HIV-1 were completely eliminated. Although HIV-BA antibody responses were markedly reduced in anti-L3T4-treated mice, anti-HIV-1 antibodies, mainly of the IgG2a isotype, were produced. The antibodies generated by HIV-1 and HIV-BA immunization were also tested for their ability to inhibit syncytia formed by infecting CD4 + CEM cells with gp160 vaccinia. Sera from normal mice, immunized with either HIV-1 or HIV-BA were capable of inhibiting syncytia. In contrast, following anti-L3T4 treatment, only mice immunized with HIV-BA, but not HIV-1, produced antibodies capable of inhibiting syncytia.

Animals↗

PubMed1991

Re-evaluation of the involvement of the adhesion molecules ICAM-1/LFA-1 in syncytia formation of HIV-1-infected subclones of a CEM T-cell leukemic line.

The role of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and LFA-1 in human immunodeficiency virus type 1 (HIV-1)-induced cell fusion was investigated in subclones of a T-cell leukemic cell line (CEM) with differing abilities to form syncytia. Addition of monoclonal antibodies 84H10 directed against ICAM-1 and MHM23 directed against the common beta subunit of LFA-1 (CD18) resulted in greater than 50% suppression of syncytia formation in cultures of these clones infected with cell-free virus. Two subclones, 2G5-144-84 and 2G5-1, were deficient in their ability to form syncytia and expressed reduced amounts of LFA-1 compared with the parental line. The expression of ICAM-1 but not LFA-1 was upregulated on the clones following treatment with interferon-gamma (IFN gamma); however, this did not overcome the delay in syncytia formation observed in these cells. The syncytia-positive subclones 1B11-39 and 17D-9 expressed high levels of LFA-1. Basal expression of ICAM-1 was upregulated on these cells by treatment with tumor necrosis factor-alpha (TNF alpha), which also accelerated and enhanced syncytia formation. However, anti-ICAM-1 and anti-LFA-1 (CD18) antibodies did not reverse the TNF alpha-induced enhancement of syncytia formation of HIV-1-infected clones 1B11-39 and 17D-9. Under conditions of low viral expression, adhesion molecules may contribute to syncytia formation if adequate levels of both receptor and ligand in the ICAM-1/LFA-1 complex are expressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗

PubMed1991

Initial stages of HIV-1 envelope glycoprotein-mediated cell fusion monitored by a new assay based on redistribution of fluorescent dyes.

Membrane fusion is an essential step in the infection of permissive cells with human immunodeficiency virus (HIV). Infected cells frequently fuse with each other, and then progress to form multinucleated giant cells (syncytia). To gain insight into mechanisms of HIV env-mediated membrane fusion, we developed a new assay for studying the initial events. The assay is based on the redistribution of fluorescent markers between membranes and cytoplasm of adjacent cells examined by means of fluorescence video microscopy. Membrane fusion between HIV-1 envelope glycoprotein (gp120/41) expressing effector cells and CD4+ target cells was observed 90 min after the association of cells, whereas the first syncytia only became apparent after 5 h. Moreover, membrane fusion events were observed under conditions where no syncytia were detected, for example, when the effector:target cell ratio was greater than 100:1, or less than 1:100. A significant number of cells with fused membranes were not involved in the syncytia. In order to determine whether quantitative differences in receptor expression might influence the extent of membrane fusion, we used laboratory-selected variants of CEM cells that differ in their expression of CD4. We found that CD4 is required on the target membrane for HIV env-mediated membrane fusion, but its extent is only partially dependent on CD4 surface concentration. The ability of those CEM variants to take part in HIV env-mediated membrane fusion did not correlate with their capacity to form syncytia. These findings indicate that additional steps are needed to form syncytia after membrane fusion.

CD4 Antigens↗

PubMed1990

Chemically induced CD4 mutants of a human T cell line. Evidence for dissociation between binding of HIV I envelope and susceptibility to HIV I infection and syncytia formation.

This study describes the derivation of a series of mutants from the human leukemic cell line CEM using the frame shift mutagen Ethyl-methanesulfonate followed by negative selection with multiple treatments of OKT4A + C, and sorting into CD4-, CD4-dull, and CD4-intermediate mutants. These mutants express reduced CD4 levels ranging from 0 to 60% of the parental line. The mutants were analyzed by staining with a battery of CD4-specific mAb, by assessing their ability to bind soluble gp120, and by their ability to form syncytia after infection with cell-free HIV I virus and a gp160-vaccinia vector. Two groups of particularly interesting mutants were identified: (1) CD4-dull mutants expressing only 5 to 10% of the wild type surface CD4 density, which nevertheless were infectable by HIV I and produced as many syncytia and reverse transcriptase activity as the parental line after infection with gp160-vaccinia or cell free HIV I. (2) CD4-intermediate mutants (30 to 60% of parental CD4 level), which express CD4-epitopes required for interaction with the HIV I envelope protein, yet are markedly deficient in their ability to form syncytia after gp160-vaccinia or HIV I infection. Two of these mutants did form syncytia after transient reconstitution with a wild type CD4 containing vaccinia vector. Inasmuch as they were found to bind soluble gp120 with the same avidity as other, functionally normal, CD4-intermediate mutants, these human T cell mutants may have a reduced susceptibility to HIV I infection due to the absence of a "fusogenic component" or to a structural alteration in a region of the CD4 molecule not required for binding of the HIV I envelope, but for the subsequent fusion and entry process.

CD4 Antigens↗

PubMed1990

CD4-derived synthetic peptide blocks the binding of HIV-1 GP120 to CD4-bearing cells and prevents HIV-1 infection.

The T cell surface glycoprotein CD4 plays an important role in mediating cellular immunity and serves as the receptor for human immunodeficiency virus. In order to identify primary sequences within the CD4 molecule that may be involved in the binding of the HIV-I envelope, we synthesized various peptides corresponding to the V1, V2, V3, and V4 domains of CD4. We tested the ability of these peptides to block the binding of purified HIV-I gp120 to CD4+ human lymphoblastic leukemia cells (CEM) using fluorescence-activated cell sorting. One of these peptides, corresponding to CD4 amino acids (74-95), when preincubated with gp120, blocked its subsequent binding to CEM cells by 80%. A truncated form of this peptide (81-95), was found to be as efficient as the longer peptide (74-95) in inhibiting the binding of gp120 to CEM cells. The same peptide did not block the binding of OKT4A or Leu3A anti-CD4 monoclonal antibodies, which were previously shown to block HIV-I binding to CD4. The peptides were also tested for their ability to block HIV-I infection of a T cell line in vitro. Only CD4 peptide (74-95) and the shorter fragment (81-95) succeeded in protecting T cells against infection with different HIV-I strains. All the other peptides examined had no effect on gp120 binding to CEM cells and did not block syncytia formation. Goat polyclonal antibodies against the CD4 peptide (74-95) gave modest interference of gp120 binding to CEM cells. These data suggest that the CD4 region (74-95) participates in the CD4-mediated binding and/or internalization of HIV-I virion.

Amino Acid Sequence↗

PubMed1990

Expression of a class I MHC transgene: regulation by a tissue-specific negative regulatory DNA sequence element.

In vivo patterns of expression of a miniature swine class I major histocompatibility gene, PD7, were analyzed both in situ in the pig, and in transgenic mice. Structural analysis of PD7 DNA sequences revealed that PD7 is highly homologous to the pig gene PD1, which encodes a classical transplantation antigen. Despite the extensive homology, PD7 is expressed in situ at markedly lower levels than PD1 in nearly all tissues. Introduction of PD7 into mice results in a pattern of PD7 expression in the transgenic animals that parallels that observed in situ in the pig. Comparison of two lines of PD7 transgenic mice, which differ only in the extent of 5' flanking sequence, reveals the presence of a silencer element. The silencer activity is tissue specific: differences in PD7 expression are observed only in lymphoid tissues and skin. Skin from both lines of transgenics mediates graft rejection, but the rate of rejection correlates with the level of PD7 expression.

Amino Acid Sequence↗

PubMed1989

Common epitope in human immunodeficiency virus (HIV) I-GP41 and HLA class II elicits immunosuppressive autoantibodies capable of contributing to immune dysfunction in HIV I-infected individuals.

We previously reported the identification of highly conserved homologous regions located in the carboxy terminus of the HIV I gp41-envelope (aa 837-844), and the amino-terminal of the beta chain of all human HLA class II antigens (aa 19-25). Murine monoclonal antibodies, raised against synthetic peptides from these homologous regions, bound not only to the isolated peptides, but also to the native gp160 and class II molecules. In this study one-third of sera from HIV I-infected individuals, at different disease stages, were found to react with both the gp41 and class II-derived peptides. These sera also reacted with "native" HLA class II molecules. The potential affects of such autoantibodies on normal immune functions were examined. It was found that in the presence of class II-cross-reactive (but not control) sera, the proliferative responses of normal CD4+ T cells to tetanus toxoid and allogeneic stimuli were markedly decreased. In addition, these sera could eliminate class II-bearing cells by antibody dependent cellular cytotoxicity. Similar affects were seen with affinity-purified IgG antibodies from patients' sera. Thus, the "molecular mimicry" between HIV I and HLA class II antigens, may lead to the generation of autoantibodies in HIV I-infected individuals that may contribute to the early functional impairment of CD4+ T cell observed in many HIV I-infected individuals.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Identification of homologous regions in human immunodeficiency virus I gp41 and human MHC class II beta 1 domain. I. Monoclonal antibodies against the gp41-derived peptide and patients' sera react with native HLA class II antigens, suggesting a role for autoimmunity in the pathogenesis of acquired immune deficiency syndrome.

Homologous regions of five amino acids each, were identified in the NH2-terminal domain of human class II beta chains and the COOH terminus of HIV I envelope protein. The homologous regions are highly conserved among different DR and DQ alleles and also among different isolates of HIV. Septamers containing these sequences were synthesized and used for the generation of murine mAbs. The mAbs selected for this study were raised against the HIV I-derived peptide and reacted strongly not only with the immunizing peptide, but also with the homologous class II-derived peptide. These mAbs also reacted with native MHC class II antigens expressed on human B cell lines and on murine fibroblast L cell lines transfected with the genes coding for the alpha and beta chains of human class II antigens. Furthermore, sera from 36% of AIDS patients tested contained antibodies that reacted with the class II-derived peptide, as well as with intact class II molecule-rich cell extracts. Such antibodies in HIV I-infected individuals may recognize self class II antigens, triggering autoimmune mechanisms that could contribute to the development of immunodeficiency in AIDS patients.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Characterization of a new subfamily of class I genes in the H-2 complex of the mouse.

A previously undescribed subfamily of mouse class I MHC genes, consisting of two to three members, has been identified. The structure and organization of one of these, Mb1, has been determined. Mb1 consists of five exons with open reading frames and potentially encodes a class I-like transmembrane protein. In the genome, Mb1 is linked to the H-2 complex, mapping telomeric to Qa. However, this gene has low (ca. 60%) nucleotide identity with other class I sequences and is no more related to mouse class I genes than to class I genes from other species. Mb1 transcripts have not been found in a variety of adult tissues or cell lines, suggesting that, if Mb1 is expressed, its expression is highly regulated. From DNA sequence identity and intron-exon organization, Mb1 appears to be a primordial gene which antedates mouse speciation and which has evolved independently of the rest of the class I gene family. Examination of various species of wild mice demonstrates the presence of a discrete Mb1 subfamily over long evolutionary periods of time.

Amino Acid Sequence↗

PubMed1987

Relationship among function, phenotype, and specificity in primary allospecific T cell populations: identification of phenotypically identical but functionally distinct primary T cell subsets that differ in their recognition of MHC class I and class II allodeterminants.

The goal of the present study was to evaluate the relationship among function, Lyt phenotype, and MHC recognition specificity in primary allospecific T cell populations. By using Lyt-2+ and L3T4+ T cells obtained from the same responder populations, we assessed the ability of T cells of each phenotype to generate cytotoxic effector cells (CTL) and IL 2-secreting helper T cells in response to either class I or class II MHC allodeterminants. It was found that a discordance between Lyt phenotype and MHC recognition specificity does exist in primary allospecific T cells, but only in one T cell subpopulation with limited functional potential: namely, Lyt-2+ T cells with cytotoxic, but not helper, function that recognize class II MHC alloantigens. Target cell lysis by these Lyt-2+ class II-allospecific CTL was inhibited by anti-Ia monoclonal antibodies (mAb), but not anti-Lyt-2 mAb, indicating that they recognized class II MHC determinants as their "restriction" specificity and not as their "nominal" specificity even though they were Lyt-2+. A second allospecific T cell subset with limited functional potential was also identified but whose Lyt phenotype and MHC restriction specificity were not discordant: namely, an L3T4+ T cell subset with helper, but not cytotoxic, function specific for class I MHC allodeterminants presented in the context of self-Ia. Thus, the present study demonstrates that primary allospecific T cell populations contain phenotypically identical subpopulations of helper and effector cells that express fundamentally different MHC recognition specificities. Because the recognition specificities expressed by mature T cells reflect the selection pressures they encountered during their differentiation into functional competence, these findings suggest that functionally distinct but phenotypically identical T cell subsets may be selected independently of one another during ontogeny. Thus, the existence of Lyt-2+ CTL specific for class II allodeterminants can be explained by the hypothesis that the association of Lyt phenotype with MHC recognition specificity results from the process of thymic selection that these Lyt-2+ effector cells avoid.

Animals↗

PubMed1987

Recognition requirements for the activation, differentiation and function of T-helper cells specific for class I MHC alloantigens.

The present review has focused on the specificity of the T-helper cell populations initiating MHC class I alloreactions. In contrast to conventional immune responses against soluble antigens, responses against membrane-bound class I alloantigens are initiated by two distinct antigen-specific T-helper cell populations that can be distinguished by their Lyt phenotype, MHC restriction specificity, antigen specificity, and requirement for thymically determined self-recognition. Alloresponses were shown to be a composite consisting of two distinct components: one mediated by L3T4+ Th cells and very similar to conventional self + X responses; and one mediated by Lyt2+ Th cells and unique to alloresponses against MHC class I antigens. As would befit an unusual Th cell population, the recognition/response spectrum of Lyt2+ Th cells was highly unusual and was found to be the basis for much of the uniqueness we attribute to immune alloreactions, including rapid rejection of tissue allografts in vivo.

Animals↗

PubMed1985

Characterization of antigen-specific, Ia-restricted, L3T4+ cytolytic T lymphocytes and assessment of thymic influence on their self specificity.

The goals of the present study were: (a) to generate antigen-specific L3T4+ cytolytic T lymphocytes (CTL), (b) to determine their major histocompatibility complex (MHC) restriction specificity, and (c) to assess the influence of thymic MHC determinants on their self specificity. We found that L3T4+ CTL specific for either trinitrophenyl (TNP)-modified self determinants or minor histocompatibility antigens could be generated from Lyt-2- responder T cells provided that the response cultures were supplemented with supernatants rich in helper factors. Such antigen-specific L3T4+ CTL were Ia-restricted by the criteria that they lysed only Ia+ target cells and that their lysis of Ia+ target cells was specifically inhibited by anti-Ia monoclonal antibodies. The relative frequency of L3T4+ pCTL was found to be only 5-10% of the total anti-TNP pCTL present in the spleens of normal mice. Finally, we utilized radiation bone marrow chimeras to assess the influence of the thymic haplotype on the self-Ia specificity of L3T4+ CTL. Both bulk culture and limiting dilution experiments revealed that the self-Ia specificity of L3T4+ anti-TNP CTL from F1----parent and A----B allogeneic chimeras was not markedly skewed toward the haplotype of the chimeric thymus. These results contrast with those obtained previously for L3T4+ anti-TNP Th cells and demonstrate that in the radiation bone marrow chimera model of T cell differentiation, the self specificity of Th cells but not pCTL is markedly influenced by the haplotype of the chimeric thymus.

Animals↗

PubMed1985

Both L3T4+ and Lyt-2+ helper T cells initiate cytotoxic T lymphocyte responses against allogenic major histocompatibility antigens but not against trinitrophenyl-modified self.

This study characterizes the T helper (Th) cells that initiate primary cytotoxic T lymphocyte (CTL) responses against allogeneic and trinitrophenyl (TNP)-modified self class I major histocompatibility (MHC) determinants. We show that two distinct Th cell subsets participate in allospecific CTL responses: (a) an L3T4+,Lyt-2- class II-restricted Th cell population, and (b) an L3T4-,Lyt-2+ class I-restricted Th cell population. Both of these T cell subpopulations were shown to function in allospecific CTL responses as helper cells by their ability to show synergy with allospecific CTL precursors. Thus, primary class I allospecific CTL responses represent an immune response involving not only L3T4+ Th cells, but Lyt-2+ Th cells as well. One of the necessary functions performed by both L3T4+ and Lyt-2+ Th cell populations in allospecific CTL responses was found to be the secretion of interleukin 2. Finally, despite the many similarities between anti-allo- and anti-TNP-CTL responses, anti-TNP-CTL responses were found to be mediated by only L3T4+ Th cells, not by Lyt-2+ Th cells. Consequently, Lyt-2+ Th cells appear to be a helper cell population that is primarily involved in MHC-specific immune responses.

Animals↗