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PubMed2007

A case-control investigation of immune function gene polymorphisms and risk of testicular germ cell tumors.

There is reason to suspect that testicular germ cell tumor (TGCT) development may be influenced by cytokines, secreted proteins that modulate tumor immune surveillance activity as well as a variety of processes in the testis. To address this hypothesis, we conducted a case-control analysis (508 cases, 608 controls) of 32 putatively functional single-nucleotide polymorphisms (SNP) in 16 immune function genes among non-Hispanic Caucasian participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. The TGFB1 Ex5-73C>T variant was positively associated with TGCT (CT/TT versus CC: odds ratio, 1.73; 95% confidence interval, 1.01-2.95; P(trend) = 0.05); additionally, haplotypes of the assessed TGFB1 SNPs (-509C>T, 327C>T, Ex1-282C>G, and Ex5-73C>T) differed in frequency between cases and controls (all TGCT, P 0.07; seminoma, P 0.04; nonseminoma, P 0.11). We also observed excess frequencies among TGCT cases versus controls of LTA 252G (P(trend) = 0.08) and of the TNF variants -1042C (P(trend) = 0.06), -1036T (P(trend) = 0.07), and -238G (P(trend) = 0.09). Analyses of haplotypes for LTA-TNF SNPs (LTA -91C>A, LTA 252A>G, TNF -863C>A, TNF -857C>T, TNF -308G>A, and -238G>A) were similarly suggestive of an association with TGCT (P = 0.06) and nonseminoma (P = 0.04), but not seminoma (P = 0.21). Polymorphisms in other genes were found to be associated only with seminoma (IL2) or nonseminoma (IFNGR2 and IL10). However, none of the associations remained noteworthy after applying the false discovery rate method to control for multiple testing. In conclusion, our findings suggest that polymorphisms in TGFB1 and LTA/TNF, and possibly other immune function genes, may influence susceptibility to TGCT.

Case-Control Studies↗
PubMed1993

Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia.

The cholinergic dysfunction present in Alzheimer's disease (AD) might be due to a specific vulnerability of cholinergic neurons linked to neurotrophic imbalance, neuroimmune impairment, and/or direct effects of beta-amyloid deposition and NFT formation in ACh neurons. The presence of abnormal epitopes exposed on neuronal membranes may contribute to the activation of resting microglia initiating a neuroimmune cascade leading to cell destruction. According to this hypothesis, a multifactorial treatment in AD should produce: 1) inhibition of beta-amyloid and NFT formation; 2) restoration of neuronal membrane integrity; and 3) control of neuroimmune auto-aggression. Since interleukin-1 (IL-1) is an APP gene promoter showing a progressive increase in body fluids in parallel with mental deterioration in AD patients, we have studied the effects of CDP-choline on cognition, several biological parameters, and IL-1 beta production in AD and multi-infarct dementia (MID) in order to elucidate whether this compound alone or in combination with other drugs is able to restore immune function and improve mental performance in senile dementia.

Aged↗
PubMed1990

Immune function in heroin addicts and former heroin addicts in treatment: pre- and post-AIDS epidemic.

These studies suggest that specific opiate receptors are not involved significantly in modulating NK-cell activity by any direct effect. The role normally played by the endogenous opioids in directly modulating NK-cell cytotoxic activity may be minimal and certainly is not a clinically relevant controlling factor. These findings also suggest that the repeatedly observed lowering of NK-cell activity in untreated heroin addicts is not due to a direct drug effect. It may be due, however, to an indirect drug effect, possibly by way of altering neuroendocrine function, which we and others have shown predictably occurs during cycles of heroin addiction, and which, as discussed above, has been shown to become normalized during steady-dose, long-term, methadone-maintenance treatment. The lowering of NK-cell activity in heroin addicts may also be due primarily to the use of unsterile needles, with exposure to and infection with multiple diseases as well as injection of many foreign substances. Clinical studies of all the important immunological indices will have to be carried out in well-characterized human populations, including normal healthy control subjects, drug abusers, drug addicts, and former drug addicts in defined treatment status, before the actual roles of drugs of abuse or drugs used to treat drug abuse in immune function in humans will be fully understood.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Relationship between amino-acid metabolism and immune functions in human lymphocytes.

Amino-acid degradation, interleukin-2 (IL-2) production, and DNA synthesis were analysed in concanavalin A (ConA)-treated peripheral venous lymphocytes from healthy blood donors and in lymphocytes from patients after uneventful abdominal surgery. ConA augmented (14)CO(2) production from (U-(14)C) glutamine (492 +/- 44 vs. 2274 +/- 174 pmol/10(6) cells x 40 min(-1)) while it had little effect on (14)CO(2) production from (1-(14)C) leucine (132 +/- 8 vs. 161 +/- 17 pmol/10(6) cells x 40 min(-1)) compared with the respective controls. Similar effects on amino-acid degradation were observed in response to surgery. Glutamine but not leucine amplified IL-2 production from ConA-treated cells, and it was a prerequisite for DNA synthesis. In lymphocytes from operated patients, spontaneous incorporation of ((3)H) thymidine was higher on day 3 and day 6 (310 and 2660 cpm/10(6) cells) after surgery, compared with the pre-operative day (68 cpm/10(6) cells; median values). These results indicate 1) that glutamine is more critical than leucine for the immune function of T-lymphocytes, and 2) that lymphocytes from patients undergoing uneventful abdomional surgery have become stimulated in vivo. It is suggested that these cells may qualify as a suitable experimental model to study the metabolic basis for immunologic functions after antigenic stimulation in vivo.

Editorial↗
PubMed1998

Dietary quercetin, immune functions and colonic carcinogenesis in rats.

Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced natural killer cell activity compared to their vehicle (VEH)-fed control. In contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen, azoxymethane had significantly reduced natural killer cell activity compared to their VEH-fed azoxymethane-treated control. There was no significant difference in natural killer cell activity between the two control groups. Antibody production and delayed-type hypersensitivity were not altered by QUE feeding in any treatment group. In vitro exposure of splenic natural killer cells to 1mM QUE significantly decreased natural killer cell cytotoxicity. Lower QUE concentrations produced a non-significant reduction in natural killer cell activity that was restored to control values at 1 x 10(-13)M QUE. The distribution, multiplicity and total number of colonic preneoplastic lesions, aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane-treated rats when compared to azoxymethane-treated vehicle-fed rats at the conclusion of 7 week feeding period. We found no correlation between immune function and development of preneoplastic colon lesions in this study.

Animals↗
PubMed2005

Initial depletion of regulatory T cells: the missing solution to preserve the immune functions of T lymphocytes designed for cell therapy.

We investigated the causes of the altered functionality of T cells cultured under conditions designed for cell and gene therapy and the strategies to prevent their defects. We first showed that human T cells cultured for 6 days with anti-CD3 +/- anti-CD28 antibodies and interleukin-2 presented a 50% decrease of their proliferative responses to allogeneic or recall antigens. Similarly, day-6 cultured murine T cells completely lost their capacity to reject allogeneic skin grafts and to provoke graft-versus-host disease (GVHD) when infused into irradiated semi-allogeneic mice. Interestingly, injection of higher amounts of cultured T cells restored GVHD induction. Moreover, depletion of CD25+ cells prior to T-cell cultures can prevent these deficiencies both in mice and humans. Therefore, we demonstrated that culture conditions used for T-cell therapy preferentially activated and expanded regulatory T cells (Treg's). Thus, we showed that dividing cells sorted from T-cell cultures strongly suppressed the proliferation of autologous T cells in response to allogeneic stimulation. An increased detection of Foxp3 at mRNA and protein levels in the cultures confirmed the Treg expansion. Overall, we demonstrate that T-cell cultures promote Treg expansion over effector T cells, leading to deleterious immune functions, and that this imbalance can be prevented by an initial depletion of CD25+ cells.

Animals↗
PubMed1985

Comparison of altered expression of histocompatibility antigens with altered immune function in murine spleen cells treated with ultraviolet radiation and/or TPA.

Previous studies in our laboratory demonstrated that several treatments that inhibited the ability of cells to stimulate the mixed lymphocyte reaction (MLR) also blocked the shedding of histocompatibility antigens and Ia antigens from murine spleen cells. In the present studies, one of these treatments, ultraviolet radiation (UV), was shown to cause an initial loss in the density of H-2K, IA, and IE antigens prior to the block in shedding observed after culture of these cells. Further analysis revealed that the UV-induced loss of antigens could be prevented by the presence of colchicine during irradiation. Biosynthetic analyses revealed the IA antigen synthesis was also inhibited in the UV-irradiated cells. Examination of the effects of a second agent, 12-0-tetradecanoylphorbol-13-acetate (TPA) on the turnover of histocompatibility antigens revealed that the biosynthesis and shedding of these antigens were accelerated by this agent. However, addition of TPA to UV-irradiated cells did not result in a reversal of the UV-induced block in biosynthesis of IA antigens. Results of immune function assays correlated with the biochemical studies: UV-irradiation inhibited the generation of the MLR, but TPA enhanced this reaction, and addition of TPA to mixed lymphocyte cultures with UV-irradiated stimulators did not reverse the UV-induced inhibition. These results suggest that, although the turnover of histocompatibility antigens may be affected by TPA and UV in an antagonistic fashion, additional factors other than the expression of histocompatibility antigens are operating in the inhibition of stimulation of an MLR by UV radiation or its enhancement by TPA.

Animals↗
PubMed1992

Time-related decrease in diffusion capacity in HIV-infected patients with impaired immune function.

The purpose of this study was to investigate acute and time-related changes in lung function, i.e. forced expiratory volume in 1 second (FEV1), vital capacity (VC) and transfer factor (KCO) in HIV-infected patients with CD4 cell counts less than 400 x 10(6)/l. 66 males with no history of HIV-related pulmonary symptoms participated in a prospective lung function study for 9 months with 3-month intervals between examinations. 15/66 patients (23%) developed acute pulmonary symptoms, i.e. dyspnea (n = 12), cough (n = 13), fever greater than 38 degrees C (n = 13) and interstitial infiltrates on the X-ray (n = 9). Among the 51 asymptomatic patients, a significant time-related decrease in KCO (median decrease of 7%) was found, whereas no significant change in FEV1 or VC was observed during the study. Baseline KCO, i.e. KCO at entry, was found to be significantly higher in the asymptomatic patients (102% predicted (pred.) than in those patients who developed pneumonia (88% pred.). Development of pulmonary symptoms was both followed by a significant decrease in KCO (median decrease 17%), FEV1 and VC. We therefore conclude that HIV-infected patients with impaired immune function have in the absence of pulmonary symptoms a decrease in KCO. In case of pneumonia an acute decrease in both KCO, FEV1 and VC occurs.

Adult↗
PubMed1987

Long-term depressed immune function in patients splenectomized for trauma.

Peripheral blood from asplenic trauma patients (ASP) was analyzed for immunoglobulin concentrations, complement levels, T- and B-lymphocyte populations, and mitogen response of T cells, and compared to a similar analysis performed on the blood of normal controls (C). The interval from splenectomy to testing averaged 1,471 +/- 193 days (mean +/- SEM) in the ASP. Total lymphocyte count averaged 2,941 +/- 234 in the ASP with a T-cell count of 2,030 +/- 182 and a B cell count of 351 +/- 58. The average control lymphocyte count of 1,769 +/- 147 was significantly less than ASP (p less than 0.001) as were the T-cell count of 1,328 +/- 107 (p less than 0.005) and the B-cell count of 124 +/- 18 (p less than 0.001). Responses to PHA were diminished in ASP lymphocytes by 38% at 3 days (p less than 0.01) and by 49% at 5 days (p less than 0.001) when compared to C. Levels of IgM were significantly decreased (p = 0.05) in ASP. Levels of C3, C4, and C5 were similar in ASP and C. These data demonstrate persistent abnormalities in immune function in adult ASP without underlying lymphoreticular disorders and suggest a possible explanation for the increased septic risk in this patient group.

Adolescent↗
PubMed2004

[An independent, non-neuronal cholinergic system in lymphocytes and its roles in regulation of immune function].

Acetylcholine (ACh) is classically thought of as a neurotransmitter in mammalian species. However, lymphocytes express most of the cholinergic components found in the nervous system, including ACh, choline acetyltransferase (ChAT), high-affinity choline transporter, and acetylcholinesterase as well as both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Activation of T cells via the T cell receptor/CD3 complex, contact of T cells with antigen presenting cells, or activation of the adenylyl cyclase pathway in T cells modulates cholinergic activity, as evidenced by up-regulation of ChAT and M(5) mAChR mRNA expression. Stimulation of mAChRs on T and B cells with ACh or another mAChR agonists elicits intracellular Ca(2+) signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and interleukin-2-induced signal transduction via M(3) and M(5) mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca(2+) signaling in T and B cells, probably via alpha7 nAChRs subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Abnormalities in lymphocytic cholinergic system have been seen in animal models of immune deficiency and immune acceleration. Collectively, these data provided a compelling picture in which immune function is, at least partly, under the control of an independent, non-neuronal cholinergic system in lymphocytes.

Acetylcholine↗
PubMed1991

Adoptive transfer of human lymphoid cells to severely immunodeficient mice: models for normal human immune function, autoimmunity, lymphomagenesis, and AIDS.

Though the development of human-to-mouse xenotransplant models is in its infancy, astonishing progress has been made in a short period of time. Two experimental applications have been developed: short-term transfer of human lymphocytes to generate models for autoimmunity and infectious diseases, and long-term engraftment of tissues with self-renewal potential. Human PBL-SCID mice have been used by multiple laboratories to study normal and autoimmune antibody responses, and have been shown to be readily infectable with HIV-1. SCID mice grafted with fetal tissue have been developed for studies of HIV-1 infection and its therapy as well as for studies of human hematopoietic cell differentiation. Human tumors appear to grow better in SCID mice than in nude mice, and hu-PBL-SCID mice can develop EBV-related B cell lymphoproliferative disease that resembles the immunoblastic lymphomas appearing in immunosuppressed transplant recipients. There is some evidence of mouse NK cells responding to the human xenograft, and of human T and B cells responding to mouse xenoantigens in these models, but these responses are not generally strong enough to have a major impact on human immune function. The use of these surrogate human models is expected to have a major impact on the understanding and treatment of human disease.

Acquired Immunodeficiency Syndrome↗
PubMed2005

A single DH gene segment creates its own unique CDR-H3 repertoire and is sufficient for B cell development and immune function.

To test the contribution of individual D gene segments to B cell development and function, we used gene targeting to create mice that contain only DFL16.1 in the DH locus. We term this D-limited IgH allele DeltaD-DFL. Although the absolute number of IgM+IgD- B cells in the bone marrow was decreased, homozygous DeltaD-DFL BALB/c mice contained normal numbers of IgM+IgD+ B cells in bone marrow and spleen and normal numbers of B1a, B1b, and B2 cells in the peritoneal cavity. Bone marrow IgM+IgD+ B cells express a CDR-H3 repertoire similar in length and amino acid composition to the DFL16.1 subset of the wild-type BALB/c repertoire but divergent from sequences that do not contain DFL16.1. This similarity in content is the product of both germline bias and somatic selection, especially in the transition to the mature IgM+IgD+ stage of development. Serum Ig concentrations and the humoral immune response to a T-dependent Ag ([4-hydroxy-3-nitrophenyl]acetyl hapten) were nearly identical to wild-type littermate controls. A greater variance in the immune response to the T-independent Ag (alpha(1-->3)-dextran) was observed in DeltaD-DFL homozygotes, with half of the mice exhibiting levels below the range exhibited by controls. Although limited to a repertoire specific to DFL16.1, the presence of a single DH gene segment of normal sequence was sufficient for development of normal numbers of mature B cells and for robust humoral immune function.

Amino Acid Sequence↗
PubMed2006

Combinations of CD45 isoforms are crucial for immune function and disease.

Expression of the CD45 Ag in hemopoietic cells is essential for normal development and function of lymphocytes, and both mice and humans lacking expression exhibit SCID. Human genetic variants of CD45, the exon 4 C77G and exon 6 A138G alleles, which alter the pattern of CD45 isoform expression, are associated with autoimmune and infectious diseases. We constructed transgenic mice expressing either an altered level or combination of CD45 isoforms. We show that the total level of CD45 expressed is crucial for normal TCR signaling, lymphocyte proliferation, and cytokine production. Most importantly, transgenic lines with a normal level, but altered combinations of CD45 isoforms, CD45(RABC/+) and CD45(RO/+) mice, which mimic variant CD45 expression in C77G and A138G humans, show more rapid onset and increased severity of experimental autoimmune encephalomyelitis. CD45(RO/+) cells produce more TNF-alpha and IFN-gamma. Thus, for the first time, we have shown experimentally that it is the combination of CD45 isoforms that affects immune function and disease.

Animals↗
PubMed1991

[Effect of zinc substitution on lymphocyte subsets and cellular immune function in hemodialysis patients].

Infection is a major cause of morbidity and mortality in patients undergoing hemodialysis for end stage renal disease. Low plasma zinc levels have been associated with immunodepression in these patients. In a randomized, placebo controlled double-blind cross over study, plasma zinc levels, delayed hypersensivity to 7 Antigens (Merieux-Multitest), absolute lymphocyte counts, T- and B-lymphocytes, suppressor-T and helper T-cells and natural killer cells were studied in 25 hemodialysis patients before, during and after intravenous zinc supplementation for 8 weeks. The hemodialysis patients had significantly lower predialysis plasma zinc concentrations compared to 76 healthy controls (74 +/- 12 vs. 126 +/- 28 mcg/dl, p less than 0.001). The plasma zinc concentrations increased to the normal range during the treatment period. Lymphocyte subtype analysis showed a significant decrease of suppressor-T cells and an increase of the helper-T/suppressor-T ratio (2.09 +/- 0.26 vs. 3.18 +/- 0.48, p less than 0.05) after zinc supplementation. Delayed hypersensivity to intradermal antigens increased significantly only after zinc treatment (2.0 +/- 0.7 vs. 5.8 +/- 1.7, p less than 0.05), not after placebo. The changes were reversible after finishing the zinc treatment. It is concluded, that plasma zinc levels are reduced in hemodialysis patients and that the substitution of zinc restores some of the depressed immune functions in these patients.

CD4-CD8 Ratio↗
PubMed1993

Effects of triptonide on mouse immune functions.

Triptonide (Tri) extracted from Tripterygium wilfordii Hook inhibited the proliferation of mouse splenocytes induced by suboptimal concentration of concanavalin A or lipopolysaccharide at concentrations of 0.02, 0.1, and 0.5 microgram.ml-1. It showed a suppressive effect on one way mixed lymphocyte culture (MLC) at 0.1-0.4 microgram.ml-1. The lymphocytes harvested from the first Tri (0.4 microgram.ml-1)-containing MLC inhibited the second MLC after being washed and irradiated with 60Co source (30 Gy). Serum anti-sheep red blood cell antibody (hemolysin) formation and clearance of charcoal particles were also suppressed by Tri in vivo. Although delayed hypersensitivity (DH) reaction to dinitrofluorobenzene (DNFB) was inhibited by Tri 1.2, 2.5, and 5.0 mg.kg-1 (ip, qd x 5 d), the spleen cell interleukin-2 secretion activities of these mice were not suppressed. Graft vs host reaction (GVHR) was not inhibited by Tri 2.5 and 5.0 mg.kg-1 (ig, qd x 5 d). Helper T cells (Th)/suppressor T cells (Ts) ratio was reduced at 2.5 mg.kg-1. The effects of Tri on mouse thymus and spleen weight were related to the age. Tri (1.2, 2.5, 5.0 mg.kg-1) had no effect on thymus and spleen weights in 8-wk-old mice. However, it increased the thymus and spleen weights in 12-wk-old mice at doses of 1.2 and 2.5 mg.kg-1. The data indicated that Tri had extensive suppressive effects on mouse immune function and its mechanism may be related to the reduction of Th/Ts ratio and the induction of Ts cells.

Animals↗
PubMed2002

CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on phenotypic and functional immune restoration in HIV-1 infection.

To evaluate the effects of the timing of highly active antiretroviral therapy (HAART) on immune reconstitution, we compared lymphocyte subpopulations and lymphocyte proliferation (LP) in response to Candida albicans, cytomegalovirus, HIV p24, Mycobacterium avium complex, pokeweed mitogen, streptokinase, and tetanus toxoid in 43 patients with pretherapy advanced, moderately advanced, and early chronic HIV-1 infection. All patients had recent CD4+ T-cell counts >450/microl and HIV RNA <400 copies/ml for >12 months. CD4+ nadirs were positively correlated with recent numbers of CD4+ T-cells (P < 0.001), memory cells (P < 0.001), and naïve CD4+ T-cells (P < 0.05) and CD4+ CD28+ T-lymphocytes (P < 0.05) and were negatively correlated with recent CD8+ T-lymphocyte counts (P < 0.05). Only CD4+ naïve T-cells normalized when HAART was initiated at lower CD4+ T-cell levels. Fifty-three percent of patients had LP responses to HIV p24 antigen. While LP responses to prevalent antigens were usually present, responses to tetanus toxoid were more common with higher CD4+ T-lymphocyte nadirs (P < 0.05). Delaying HAART may limit phenotypic and functional immune restoration in HIV-1 infection.

Adult↗
PubMed2003

Role of the CD5 molecule on TCR gammadelta T cell-mediated immune functions: development of germinal centers and chronic intestinal inflammation.

Although CD4(+) T cells form a major subset of TCRalphabeta T cells, only a small number of TCRgammadelta T cells express CD4. Factors contributing to the down-regulation of CD4(+) TCRgammadelta T cells have not been identified. The CD5 molecule is expressed on most TCRgammadelta T cells in the spleen, whereas only a few intestinal intraepithelial TCRgammadelta T cells express this molecule in wild-type mice and TCRbeta mutant (beta(-/-)) mice. Unexpectedly, in the present studies, the lack of CD5 led to a remarkable increase of a CD4(+) TCRgammadelta T cell subset in CD5(-/-)beta(-/-) mice. The CD4(+) TCRgammadelta T cells were also detectable in MHC II(-/-)CD5(-/-)beta(-/-) triple-mutant mice. This CD4(+) TCRgammadelta T cell subset provided help in Mycobacterium-induced germinal center (GC) formation and showed a T(h)-like cytokine profile. In contrast, CD5(+) TCRgammadelta T cells suppressed the CD4(+) TCRgammadelta T cell-mediated GC formation, presumably by eliminating this CD4(+) subset. Unlike intraepithelial gammadelta T cells, >30% of TCRgammadelta T cells in the colonic lamina propria (LP) expressed CD5. The lack of CD5 also led to increased numbers of CD4(+) TCRgammadelta T cells in the colonic LP and increased susceptibility to development of chronic colitis in beta(-/-) mice. Cell transfer studies suggest that CD5(+) TCRgammadelta T cells are capable of selectively eliminating CD4(+) TCRgammadelta T cells in the intestine. The CD4(+) TCRgammadelta T cells possess immune functions similar to CD4(+) TCRalphabeta T cells.

Animals↗
PubMed1991

Abnormal thymic development, impaired immune function and gamma delta T cell lymphomas in a TL transgenic mouse strain.

During derivation of transgenic mouse strains with various TL and TL/H-2 chimeric genes, one strain, Tg.Tlaa-3-1, introduced with a TL gene (Tlaa-3), was found to have an abnormal thymic T cell population and to develop a high incidence of T cell lymphomas. To investigate the etiology of the thymic abnormalities and of the lymphomas, the development of lymphoid organs in transgenic mice was studied. The thymus of these mice goes through three unusual successive events: perturbation of thymic development during embryogenesis, disappearance of thymocytes between day 14 and day 21 after birth, and subsequent proliferation of large blast-like cells. These events are associated with the abolishment of T cell receptor (TCR) alpha beta lineage of the T cell differentiation, leading to preponderance of cells belonging to the TCR gamma delta L3T4-Lyt-2- double negative (DN) lineage. Bone marrow transplantation and thymic graft experiments demonstrate that the abnormality resides in the bone marrow stem cells rather than in the thymic environment. The expression of TL antigen in the transgenic mice is greatly increased and TL is expressed in a wide range of T cells, including normally TL- DN cells and L3T4+ Lyt-2- and L3T4-Lyt-2+ single positive cells. These quantitative and qualitative abnormalities in TL expression most likely cause the abnormal T cell differentiation. The gamma delta DN cells migrate into peripheral lymphoid organs and constitute nearly 50% of peripheral T cells. Immune function of the transgenic mice is severely impaired, as T cell function is defective in antibody production to sheep red blood cells, in mixed lymphocyte culture reaction to allogenic spleen cells and also in stimulation with concanavalin A. These results indicate that the gamma delta cells are incapable of participating in these reactions. Molecular and serological analysis of T cell lymphomas reveal that they belong to the gamma delta lineage, suggesting that the gamma delta DN cells in this strain are susceptible to leukemic transformation. Based on cell surface phenotype and TCR expression of the DN thymocytes and T cell lymphomas, a map of the sequential steps involved in the differentiation of gamma delta DN cells is proposed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗