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C A Janeway

Publications and source records attributed to C A Janeway.

At least 271 records · Page 15Linked to original sources
PubMed1980

Cell cooperation during in vivo anti-hapten antibody responses. VI. Evidence for an allogeneic effect replacing one of two helper T cells.

T and B lymphocyte activity in adoptive secondary antibody responses was assessed by cell titration in mice of the X-linked immune defective CBA/N strain and mice of their normal partner strain CBA/CaJ. No quantitative differences could be detected in either T or B cell activity in these experiments, in which 2,4-dinitrophenyl was used as the hapten. Both of the helper T cells detected in such assays were present in both strains. During these experiments, it was found that a subline of CBA/N maintained at Yale may have diverged from the CBA/N NIH stock. This was detected by an ability of irradiated mice of the Yale subline to increase the antibody response of B cells from the NIH subline, provided specific helper T cells were also present. This allogeneic effect apparently replaced the activity of one helper T cell, but did not replace the requirement for a carrier-specific helper T cell.

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PubMed1980

Idiotypes, T-cell receptors, and T-B cooperation.

T cells are responsible for virtually all the characteristics of the mammalian immune system except the production of serum antibody, in which they play a vital regulatory role. As such, they are central to our understanding of the immune system. T cells recognize cell-bound antigens with great precision, in association with self MHC antigens. They do this by means of antigen-specific receptors, whose antigen-combining sites are encoded in conventional VH genes. There is evidence that T cells carry at least two kinds of specific receptors, one for MHC antigens and one for non-MHC antigens. Both of these would bear VH-encoded and distinct idiotypic determinants. The process by which antigens associate with MHC-gene products on cell surfaces is poorly understood at present, and so is the process by which the two types of receptors communicate with each other. T cells are divisible into a number of subpopulations playing unique functional roles in the regulation of antibody responses. If one examines them further for other functions, even greater complexity emerges. Thus, all T cells may not have the same kind of receptor, which would not be surprising given the wide variety of functions they perform. Future work will undoubtedly focus on these important questions.

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PubMed1979

Helper T cell interactions.

Studies of the relationship between carrier-primed helper T cell dose and the antibody response to a hapten on that carrier reveal evidence for two synergistic T helper cells. One of these two T cells is absent in agammaglobulinemic mice. This finding is not due to suppression; instead, T helper cells from these mice interact synergistically with T helper cells from normal mice, as would be predicted if two populations of cells are present in normal mice, while only one is present in the agammaglobulinemic mice. These findings, taken together with studies in similar systems, suggest that one of the two T helper cells recognizes immunoglobulin on B cells, while the other is specific for carrier. It remains to be determined whether both cells show the phenomenon of major histocompatibility complex restriction, or whether this a property of one of the cells only. It is also not clear whether the Ig-recognizing T cell is also carrier specific, or whether its apparent carrier specificity in this system reflects an ability of the carrier to bring together Ig and an I region gene product into a unique configuration on the B cell surface.

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PubMed1979

Experimental malaria in the CBA/N mouse.

CBA/N mice carry an X-linked, recessive gene, which results in the absence of a B cell subset, and is expressed primarily as an inability to respond to a certain class of thymus-independent antigens. We have examined the responses of these mice to the malaria parasite Plasmodium yoelii and found that primary infections induced by this parasite are more severe and last longer in mice with X-linked defect than in normal controls. The decreased resistance of the defective mice is associated with a striking deficiency in their IgM antibody response. After recovery from a primary infection, defective mice resist reinfection with the homologous parasite as well as normal mice. Although as resistant as normal controls, B cells from defective mice transfer considerably less immunity to naive recipients than B cells from normal animals. Hence, two modes of thymus-dependent protective immunity may contribute to the host response to P. yoelii. Control of an acute primary infection appears to involve a thymus-dependent antibody response that CBA/N mice are deficient in. Resistance to reinfection may be mediated primarily by a different mechanism.

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PubMed1978

T cells specific for hapten-modified self are precommitted for self major histocompatibility complex antigens before encounter with the hapten.

The technique of antigen-driven, 5-bromo-deoxyuridine and light suicide has been adapted to eliminate the precursors of cytotoxic effector cells both for alloantigen and for 2,4,6-trinitrophenyl(TNP)-modified stimulator and target cells. Using this technique, the following observations have been made. Precursors of killer cells specific for alloantigen can be suicided independently of precursors of killer cells specific for TNP-modified self cells. The loss of activity during this procedure is not due to either specific or nonspecific suppressor cells, as judged by mixing experiments. With responder cells from F1 animals, it has been possible to show that precursors specific for TNP-modified cells from one parent are suicided independently of precursors specific for TNP-modified cells of the other parent, but only if the parental strains differ in the K and D regions of the H-2 complex. Cells of F1 mice derived from K and D identical, I region different, parental strains were specifically suicided by TNP-modified stimulator cells from either parent. However, the cross-reactive killing of TNP-self targets induced by stimulation with allogeneic cells is not eliminated by first suiciding with TNP-parental cells, suggesting that the precursors of these two types of TNP-self killer cells are different. This is compatible with reported differences in their specificity, as confirmed in this report. Finally, deletion of alloreactive cells by this technique reveals little or no reactivity specific for TNP-modified allogeneic stimulator cells. In summary, these results strongly suggest that recognition of self MHC antigens is preprogrammed in peripheral T cells of normal animals, and is not acquired during the immunization process. They also suggest that cells specific for modified alloantigen are relatively rare in the strains of mice studied.

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PubMed1977

Evidence for an immunoglobulin-dependent antigen-specific helper T cell.

Evidence from various systems suggests that thymus-derived lymphocytes can affect the quality of antibody responses by recognizing various portions of the immunoglobulin receptor of bone-marrow-derived thymus-independent lymphocytes. A model for this process is proposed involving two antigen-specific mature T helper cells, one of which also is specific for immunoglobulin determinants. These two cells act synergistically. Evidence from adoptive secondary antibody responses demonstrates that both cells are antigen-specific T cells and that the immunoglobulin-recognizing T helper cell is absent from experimentally agammaglobulinemic mice. This cell is termed an "immunoglobulin-dependent T cell" because its activation requires the presence of immunoglobulin.

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PubMed1977

Immune responses of BALB/c mice to the idiotype of T15 and of other myeloma proteins of BALB/c origin: implications for an immune network and antibody multispecificity.

Normal adult BALB/c mice are virtually unresponsive to the idiotype of myeloma protein T15 when immunized with purified T15. However, antibodies to the T15 idiotype can be elicited by T15 in BALB/c mice that are reared in a germ-free environment or injected as newborns with an alloantiserum to the idiotype. Some germ-free and neonatally suppressed mice also produce helper cells (presumably T helpers) that enhance B-cell production of anti-DNP antibodies in response to DNP-T15. Taken together with previous studies, the present results mean that so far there are no exceptions to the rule that BALB/c mice have B and T cells that can respond to idiotypes of myeloma proteins of BALB/c origin. There appears to be a reciprocal relation between the natural prevalence of an immunoglobulin's idiotype and its immunogenicity in isologous individuals. The findings support proposals for an immune network of idiotypes and anti-idiotypes. Besides binding one or more extrinsic antigens, it is likely that each immunoglobulin also binds the idiotype of some other immunoglobulin. An immune network therefore implies multispecificity of antibodies.

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PubMed1976

The specificity of cellular immune responses II. The structure of antigenic determinants leading to T-lymphocyte stimulation.

T cells from guinea pigs immunized with the hapten 2,4-dinitrophenyl (DNP)-coupled directly to mycobacteria are of interest since they recognize and respond to DNP conjugated to many but not all carriers. The experiments reported here further analyze the structure of the complex, chemically defined antigenic determinants recognized by such T cells. These antigenic determinants can have DNP coupled either to the xi-amino group of lysyl residues or to the hydroxyl group of tyrosyl residues. Furthermore, essential contributions to the determinant recognized by such T cells are made by amino acid residues to which the hapten is not attached. Such residues are thought to be close to the hapten group itself, since introducing a small spacer between hapten and carrier prevents recognition. The hapten itself is also recognized and discriminated from other haptens with great precision by these T lymphocytes. The strain of guinea pig immunized affects the precise specificity characteristics of the responding T cells, in a way that may reflect the activity of histocompatibility-linked immune response genes. Finally, the characteristics of the immunogen have been studied. It is thought that the lipid content of the mycobacteria may be critical in inducing the hapten-reactive T cells, and this is supported by finding similar responses in T cells from guinea pigs immunized with DNP protein to which lipid has been covalently attached. Thus, the T-cell population being studied, while recognizing haptens with great precision, appears to require a larger determinant for activation than do hapten-specific B lymphocytes.

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PubMed1976

The specificity of cellular immune responses in guinea pigs. III. The precision of antigen recognition by T lymphocytes.

T lymphocytes from guinea pigs immunized with 2,4-dinitrophenyl (DNP) derivatives of mycobacteria respond to a variety of DNP conjugates. Preincubation of such cells with a given DNP conjugate under conditions which lead to the inactivation of responding cells causes a loss of the response to that conjugate, but has little effect on the response to DNP coupled to unrelated carriers. Thus, the responses of such cells to a variety of DNP conjugates can best be explained by the presence of a mixture of highly specific cells each responding to a different antigenic dterminant rather than by the presence of T cells with specificity limited to the hapten itself. Furthermore, the activity of T cells from DNP-mycobacteria-primed donors could not be blocked by a variety of nonstimulatory DNP conjugates. This suggests that while such T cells clearly recognize DNP with great precision, the receptor does not contain a very high affinity site for the hapten. A possible model for such a T-cell receptor is discussed.

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PubMed1976

Isolation of antigen-binding cells from unprimed mice. II. Evidence for monospecificity of antigen-binding cells.

Spleen cells from unimmunized mice were exposed to two contrastingly fluorescent antigens simultaneously. Antigen-binding cells of either specificity were isolated using a fluorescence-activated cell sorter (FACS). Purified cells binding one or the other of the antigens were then examined by fluorescence microscopy for the presence of bound antigen of the alternate specificity. No double binding cells were seen. If cells bear receptors of two or more specificities and these receptors are randomly distributed among antigen-binding cells, then of the 13 000 binding cells examined 82 were expected to bind both antigens. These results strongly suggest that antigen-binding cells bear receptors of only one specificity. In addition, by inference from the functional correlation between antigen-binding cells and precursor cells, the data support the contention that precursors of antibody-forming cells are monospecific.

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PubMed1976

Specific loss of stimulator activity following mixed lymphocyte reactions is due to cytotoxic cells.

Experiments were performed to test the hypothesis that stimulating antigens in the mixed lymphocyte reaction (MLR) are expressed in a restricted fashion on lymphocytes. Thus one-way MLR between spleen cells from congenic mouse strains differing at H-2 were treated with 5-bromo-2-deoxyuridine (BrdUrd) and light to inactivate dividing cells. The ability of the residual cells to act as responder or stimulator cells in a subsequent MLR was assessed. As expected, a specific loss of responder cell activity occurred under these conditions. Furthermore, such cells, following irradiation, would not stimulate fresh spleen cells from the strain against which they initially responded, but would stimulate spleen cells, following irradiation, would not stimulate fresh spleen cells from the strain against which they initially responded, but would stimulate spleen cells of unrelated mouse strains. This was shown to be due to the generation of cytotoxic T cells detectable in 51Cr release assays in the primary MLR, despite BrdUrd and light treatment and irradiation. Furthermore, loss of stimulator activity mapped to the H-2K region of the H-2 complex rather than the strong MLR-stimulating I-A or I-B subregions. These experiments provide no evidence of restricted expression of MLR-stimulating antigens on lymphocytes.

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PubMed1976

Specific and nonspecific cooperation between M-locus-incompatible T and B cells during adoptive anti-hapten antibody responses in mice.

CBA and AKR mice are identical at the major histocompatibility locus (H-2) but differ at the strong, non-H-2, mixed leukocyte culture (MLC)-stimulating M-locus. Adoptive secondary in vivo antibody responses using immune spleen cells from mice of these strains demonstrate two interesting findings. One is a non-specific augmentation of the anti-hapten antibody response of CBA B cells by AKR T cells. This allogeneic effect is unidirectional in the same sense as the MLC between cells from these two strains. The second is that, despite an ongoing allogeneic effect, M-locus-incompatible T and B cells show strong specific cooperation. Thus, it seems unlikely that the failure of H-2-incompatible T and B cells to collaborate specifically is due to inhibitory allogenic reactions.

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