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PubMed2004

Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease in which myelin-specific T cells are believed to play a crucial pathogenic role. Nevertheless, so far it has been extremely difficult to demonstrate differences in T cell reactivity to myelin Ag between MS patients and controls. We believe that by using unphysiologically high Ag concentrations previous studies have missed a highly relevant aspect of autoimmune responses, i.e., T cells recognizing Ag with high functional avidity. Therefore, we focused on the characterization of high-avidity myelin-specific CD4+ T cells in a large cohort of MS patients and controls that was matched demographically and with respect to expression of MHC class II alleles. We demonstrated that their frequency is significantly higher in MS patients while the numbers of control T cells specific for influenza hemagglutinin are virtually identical between the two cohorts; that high-avidity T cells are enriched for previously in vivo-activated cells and are significantly skewed toward a proinflammatory phenotype. Moreover, the immunodominant epitopes that were most discriminatory between MS patients and controls differed from those described previously and were clearly biased toward epitopes with lower predicted binding affinities to HLA-DR molecules, pointing at the importance of thymic selection for the generation of the autoimmune T cell repertoire. Correlations between selected immunological parameters and magnetic resonance imaging markers indicate that the specificity and function of these cells influences phenotypic disease expression. These data have important implications for autoimmunity research and should be considered in the development of Ag-specific therapies in MS.

Adult↗

PubMed2006

Cutting edge: allogeneic CD4+CD25+Foxp3+ T regulatory cells suppress autoimmunity while establishing transplantation tolerance.

An important unresolved question with regard to T regulatory (Treg) cell specificity and suppressive activity is whether allogeneic Treg cells inhibit self-reactive T cells. In the present study, this issue was addressed using IL-2Rbeta-deficient mice that develop rapid lethal autoimmunity due to impaired production of Treg cells. We show that adoptive transfer of completely MHC-mismatched Treg cells into IL-2Rbeta(-/-) mice resulted in life-long engraftment of the donor cells, which exhibited skewed reactivity toward host alloantigens, and prevented autoimmunity. Thus, Treg cells that underwent thymic selection by peptide/MHC class II complexes distinct from those recognized by autoreactive T cells, still effectively suppress autoimmunity. Remarkably, when such animals were skin grafted, they exhibited dominant tolerance to those grafts bearing MHC molecules that were shared with donor Treg cells. Collectively, these data demonstrate that effective engraftment by allogeneic Treg cells controls autoimmunity and results in permissive conditions for long-term acceptance of allografts.

Adoptive Transfer↗

PubMed2006

Alternative translational products and cryptic T cell epitopes: expecting the unexpected.

Although CD8 T cell epitopes have been studied extensively, often overlooked are unconventional cryptic epitopes generated from nontraditional sources of peptides/proteins and/or mechanisms of translation. In this review, we discuss alternative reading frame epitopes, both mechanistically and also in terms of their physiologic importance in the induction of antiviral and antitumor CTL responses. Issues of the influence of cryptic translational products on foreign and self-Ag diversity, thymic selection, and the T cell repertoire; disease pathogenesis; and approaches to vaccine design are discussed in context of the potentially large impact of unconventional epitopes on T cell immunity.

Animals↗

PubMed1999

Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance.

This study shows that the normal thymus produces immunoregulatory CD25+4+8- thymocytes capable of controlling self-reactive T cells. Transfer of thymocyte suspensions depleted of CD25+4+8- thymocytes, which constitute approximately 5% of steroid-resistant mature CD4+8- thymocytes in normal naive mice, produces various autoimmune diseases in syngeneic athymic nude mice. These CD25+4+8- thymocytes are nonproliferative (anergic) to TCR stimulation in vitro, but potently suppress the proliferation of other CD4+8- or CD4-8+ thymocytes; breakage of their anergic state in vitro by high doses of IL-2 or anti-CD28 Ab simultaneously abrogates their suppressive activity; and transfer of such suppression-abrogated thymocyte suspensions produces autoimmune disease in nude mice. These immunoregulatory CD25+4+8- thymocytes/T cells are functionally distinct from activated CD25+4+ T cells derived from CD25-4+ thymocytes/T cells in that the latter scarcely exhibits suppressive activity in vitro, although both CD25+4+ populations express a similar profile of cell surface markers. Furthermore, the CD25+4+8- thymocytes appear to acquire their anergic and suppressive property through the thymic selection process, since TCR transgenic mice develop similar anergic/suppressive CD25+4+8- thymocytes and CD25+4+ T cells that predominantly express TCRs utilizing endogenous alpha-chains, but RAG-2-deficient TCR transgenic mice do not. These results taken together indicate that anergic/suppressive CD25+4+8- thymocytes and peripheral T cells in normal naive mice may constitute a common T cell lineage functionally and developmentally distinct from other T cells, and that production of this unique immunoregulatory T cell population can be another key function of the thymus in maintaining immunologic self-tolerance.

Animals↗

PubMed1999

A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes.

MHC class II molecules have a crucial role in thymic selection and in generating Ag-specific T cell responses. There is extensive evidence for second messenger generation via MHC class II molecules, which can lead to apoptosis of B lymphocytes. We have examined HLA class II-mediated apoptosis in both normal and tumoral human B lymphocytes. Phosphatidylserine exposure and DNA fragmentation were observed in B cells within 24 h of stimulation via HLA class II. In marked comparison with Fas, the cell-permeable and irreversible caspase inhibitors zVAD-fmk and DEVD-fmk failed to inhibit HLA-DR-mediated apoptosis. No direct activation of caspase 3 was detected, and cleavage of pro-caspase 3 was not observed. Cleavage of poly(ADP-ribose) polymerase was detected via Fas but not via HLA class II. Although phosphatidylinositol-3-kinase has been implicated in HLA class I-mediated apoptosis, neither wortmannin nor LY294002 affected HLA class II-mediated apoptosis. CD95-sensitive cells were used to reveal that death occurred independently of CD95-CD95 ligand interactions. Overall, these data reveal a pathway of HLA-DR-mediated apoptosis that neither requires nor involves caspases. Moreover, it is phosphatidylinositol-3-kinase independent and Fas/CD95 independent. This pathway of HLA class II-mediated apoptosis could have an important role in the regulation of APC populations or in the control of malignant B lymphocyte proliferations.

Amino Acid Chloromethyl Ketones↗

PubMed1999

Apoptosis and cell death in the endocrine system.

Inflammatory diseases of the endocrine system--such as thyroiditis, diabetes, and Graves' disease--are considered to be autoimmune in origin. More recently, these and other autoimmune diseases have been associated with defects in Fas apoptosis. The mutation of the Fas or Fas ligand (FasL) has been observed in a minority of patients with autoimmune disease. However, dysfunction of the Fas apoptosis signaling pathway or production of soluble factors, including sFas and sFasL, may be more prevalent. Certain endocrine tissues, such as the testes, are immune privilege sites. Defects in Fas and FasL expression in immune privilege sites can trigger an inflammatory response. Other factors that trigger inflammatory diseases of the thyroid or islets may be loss of self tolerance, leading to an autoimmune response. An infectious trigger or other environmental agent can initiate organ damage, leading to release of new antigens that initiate the autoreactive process. We have developed a murine cytomegalovirus model of Sjögren's syndrome in which defects in the Fas/FasL pathway are necessary to enable chronic inflammation, even after the initial virus has been cleared. Another interaction between the endocrine system and apoptosis is by direct hormone interaction. This is exemplified by the orphan steroid receptor Nur77. Nur77 is important for T cell apoptosis after signaling through CD3. We have demonstrated that a dominant-negative Nur77 transgenic mouse exhibits a defect in thymic selection of T cells. Therefore, there are many potential mechanisms by which endocrine glands or hormones can affect the Fas apoptosis pathway, resulting in either cell death or a chronic inflammatory disease in the endocrine system, leading to hypothyroidism and diabetes. This inflammatory dysfunction can be reversed by a dominant-negative I kappa B that prevents nuclear translocation of NF-kappa B. We have developed antigen-specific, antigen-presenting cells that express high levels of FasL that can prevent tissue-specific inflammatory disease. Treatment with these cells prevents development of diabetes in NOD mice. Further understanding of the role and regulation of apoptosis in diseases of the endocrine system (e.g., diabetes, thyroiditis) should lead to better methods of treatment and prevention of these diseases.

Animals↗

PubMed1999

8B4/20, a private CD43 epitope on developing human thymocytes, is involved in thymocyte maturation.

The 8B4/20 Ag is a 120-kDa molecule whose expression on human thymocytes varies according to the differentiation stage: high density on immature CD3-/low thymocytes, reduced density on CD3medium and double-positive thymocytes, and absent on CD3high and single-positive thymocytes and on circulating T cells. In this paper we present immunological and biochemical evidence demonstrating that 8B4/20 Ag is a variant of CD43. We show that 8B4/20-expressing molecules, which are a subset of the CD43 molecules on thymocytes, are heterogeneous in charge, suggesting varying sialylation levels. The 8B4/20 epitope was mapped to the peripherally exposed N-terminal region of CD43, and the 8B4/20 antigenic determinant was characterized by requirement for the sialic acid exocyclic polyhydroxyl side chain, a feature shared with ligands of CD22. Altogether, 8B4/20-CD43 expression pattern and biochemical characteristics suggest its participation in carbohydrate-based interactions in the thymus. We therefore used specific Ab to mimic putative 8B4/20 interactions with natural ligand and examined the effect on isolated thymocytes. Treatment with 8B4/20 had no effect on in vitro apoptosis of isolated thymocytes. In contrast, 8B4/20 ligation enhanced the conversion of isolated thymocytes to differentiated phenotypes. Increased numbers were found in 8B4/20-treated cultures of CD3high and single-positive thymocytes and decreased numbers of CD3-/low and double-positive thymocytes, strongly suggesting that engagement of 8B4/20 delivers a positive signal that favors completion of the thymocyte maturation program. The ability of 8B4/20 mAb to drive thymocyte maturation in vitro suggests that CD43 molecules bearing the 8B4/20 epitope participate in early events of thymic selection.

Antibodies, Monoclonal↗

PubMed1999

Transcriptional control of MHC genes and T cell development in MHC class II deficiency.

MHC class II deficiency has proven to be an excellent model to study transcription regulation of MHC genes and T cell development. Cell lines established from MHC class II deficient patients have been of great value for the identification of proteins necessary for MHC expression and their study has resulted in the identification of a common regulatory pathway for MHC class II and class I genes. The lack of MHC class II expression was found to have a profound effect on the development of the CD4+ T cell lineage, in particular on the composition of the T cell receptor repertoire, revealing aberrant thymic selection processes in these patients. Here, we will discuss several aspects of the transcriptional regulation of MHC genes and the impact of deficient MHC class II expression on T cell development.

CD4-Positive T-Lymphocytes↗

PubMed2000

[The role of adhesion molecules in the immune system].

Adhesion molecules play a major role in many biological functions. They are crucial in the development of embryo into formed organism; later they mediate many physiological and pathological functions. From the immunological point of view they are involved in virtually every process of cell interactions, involving thymic selection and antigen priming, antigen recognition and cell activation, cytotoxicity and lymphocyte recirculation. This review focuses mainly on the role of adhesion molecules in close contact between the cells, crucial for the inflammatory and immune responses. (Tab. 3, Fig. 1, Ref. 29.)

Cell Adhesion Molecules↗

PubMed1992

[Immunologic mechanisms implicated in autoimmune destruction of beta cells in type I diabetes].

Lymphocytic infiltration of the islets of Langerhans results from activation of immunity effector cells during the period preceding clinical onset of diabetes. After escape from thymic selection, the autoreactive cell clones proliferate in the peripheral hemopoietic organs prior to invading the islets of Langerhans. The selection, expansion and activation of autoreactive cells are under genetic control. The development of quantitative tests of cellular immunity should allow determination of the importance of the anti-islet immunologic reaction, suspected at present from the presence of specific autoantibodies in genetically predisposed subjects at high risk of insulin dependence.

Autoimmunity↗

PubMed1992

Deletion of antigen-specific immature thymocytes by dendritic cells requires LFA-1/ICAM interactions.

An in vitro assay was used for assessing the participation of various cell surface molecules and the efficacy of various cell types in the deletion of Ag-specific immature thymocytes. Thymocytes from mice expressing a transgenic TCR specific for the male Ag presented by the H-2Db class I MHC molecule were used as a target for deletion. In H-2d transgenic mice, cells bearing the transgenic TCR are not subjected to thymic selection as a consequence of the absence of the restricting H-2Db molecule but, nevertheless, express this TCR on the vast majority of immature CD4+8+ thymocytes. In this report we show that CD4+8+ thymocytes from H-2d TCR-transgenic mice are preferentially killed upon in vitro culture with male APC; DC were particularly effective in mediating in vitro deletion when compared with either B cells or T cells. Deletion of CD4+8+ thymocytes by DC was H-2b restricted and could be inhibited by mAb to either LFA-1 alpha or CD8. Partial inhibition was observed with mAb to ICAM-1, whereas mAb to CD4 and LFA-1 beta were without effect. These results are the first direct evidence of LFA-1 involvement in negative selection and provide further direct support for the participation of CD8/class I MHC interactions in this process. Like the requirements for deletion, activation of mature male-specific CD4-8+ T cells from female H-2b TCR-transgenic mice was also largely dependent on Ag presentation by DC and required both LFA-1/ICAM and CD8/class I MHC interactions; these results support the view that activation and deletion may represent maturation stage-dependent consequences of T cells encountering the same APC. Finally, our results also support the hypothesis that negative selection (deletion) does not require previous positive selection because deletion was observed under conditions where positive selection had not occurred.

Animals↗

PubMed1992

SCID-hu mice as a model to study tolerance after fetal stem cell transplantation.

SCID-hu mice were constructed with human fetal liver and human fetal thymus, obtained from the same or from different donors. Hematopoietic cells originating from the fetal liver migrate to the fetal thymus and give rise to medullary and cortico-medullary macrophages and dendritic cells. Thymic epithelial cells remain of thymic donor origin. The fetal liver donor derived stem cells differentiate in this environment into double positive and finally single positive CD4 or CD8 expressing T cells. The TCR V beta repertoire generated at the double positive stage is identical to that generated in the thymus of the donor. Thymic selection induces changes in V beta usage comparable to those previously reported for normal human thymus. Single-positive, functionally mature, and mainly TCR alpha beta+ T cells reach the peripheral blood compartment of the SCID-hu mice. These T cells are able of specific proliferative and cytotoxic alloresponses. No autoreactivity is observed. Single positive T cells which differentiated in the thymus of SCID-hu mice transplanted with liver and thymus of two different donors are tolerant to the HLA antigens of both donors. By limiting dilution analysis, it could be demonstrated that tolerance to the fetal liver donor is due to clonal deletion whereas tolerance to the fetal thymus donor is not. These data show that human T cell development is progressing normally in these mice and gives rise to a mature, functional and polyclonal T cell repertoire which is comparable to that observed in normal individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Multiple types of cytokines constitutively produced by an established murine thymic epithelial cell line.

An untransformed murine thymic epithelial cell line (MTEC1) has been established. Without exogenous stimulation, the MTEC1 cells constitutively produced multiple types of cytokines, including IL-1, IL-6, IL-7, GM-CSF and chemotactic factor(s). Of which, IL-6, GM-CSF and chemotactic factor(s) were abundant; IL-1, moderate; and IL-7 at low level. MTEC1 cells neither produced detectable IL-3 nor TNF alpha. Thus, the MTEC1 cells may be useful not only in the evaluation of the signals required for thymic selection in vitro, but also useful in the analysis of the endogenous regulation of the autocrine cytokine production cascade.

Animals↗

PubMed1991

[Activation of CD4+ T-lymphocytes in asymptomatic HIV infected patients induce the program action of lymphocyte death by apoptosis].

Activation-induced programmed cell death, or apoptosis, is a physiological cell suicide process involved in the negative thymic selection of the T-cell repertoire. We have proposed that the inappropriate re-emergence in the mature CD4+ T-cell population of such a death program could explain both the early dysfunction and the late depletion of CD4+ T-cells from human immunodeficiency virus (HIV)-infected individuals. We present evidence showing that the selective failure of T-cells from 10 HIV-infected asymptomatic individuals (with normal CD4+ T-cell counts) to proliferate in vitro to pokeweed mitogen and to self-major histocompatibility complex class-II T-cell receptor mobilization by superantigens is due to the induction by these stimuli of CD4+ T-cell death. This death process has characteristic features of apoptosis, including DNA fragmentation into multiples of a 200 base pair unit, and the preventive effect of the protein synthesis inhibitor cycloheximide. These findings suggest that in vivo CD4+ T-cell suicide upon activation might account, independently of any HIV-mediated cytopathic effect, for the progressive depletion of CD4+ T-cells that leads to AIDS.

CD4-Positive T-Lymphocytes↗

PubMed2006

Expression of the membrane complement regulatory proteins (CD55 and CD59) in human thymus.

CD59 is one of the key molecules involved in cell protection against autologus complement. The fact that complement regulatory proteins are able to prevent hyperacute rejection of organs in pig to primate model, raises the question of possible complement regulatory protein (CRP) involvement in the maturation of immunological system. We report here that in foetal and postnatal human thymus, CD59 and CD55 are primarily located on Hassall's corpuscles and medullary epithelial cells. This localization highly correlates with the expression of CD30L, which is the member of the tumour necrosis factor superfamily. Additionally, TUNEL technique was used to visualize distribution of apoptotic cells in the thymus, which revealed the presence of apoptotic cells closely associated with the Hassall's corpuscles. The observed co-localization of CD59, CD55 and CD30L might suggest an involvement of the complement system in thymic selection in humans.

Adolescent↗

PubMed1992

The relationship between AIDS and immunologic tolerance.

A hypothesis is presented in which the immunodeficiency and cell loss leading to acquired immune deficiency syndrome and the clonal deletion associated with immunologic tolerance occur through a common mechanism. In a previous publication we proposed that the interaction of human immunodeficiency virus (HIV) with CD4 delivers activation signals that disrupt immune system regulation. In this article, we compare the biology of HIV infection with recent discoveries concerning the "two-signal" molecular mechanism for thymic selection. We propose that two-signal activation is normally followed by clonal expansion and the programmed death of most or all daughter cells through mechanisms that are proportional to the strength and duration of the activation signals. In the thymus, self-reactive cells are trapped in the continuous presence of both antigen signals (signal 1) and costimulatory signals (signal 2), leading to clonal deletion. In mature lymphocytes, we propose that HIV infection contributes a chronic high-affinity signal 2, which shifts the equilibrium of antigen-activated T-cell populations further toward programmed death. This leads to incremental memory cell deficits and gradual clonal deletion at a rate dependent on the frequency of antigen exposure and the ability of an HIV quasispecies to induce signal 2.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Deviations in thymocyte development induced by divalent and monovalent ligation of the alpha/beta T cell receptor and by its cross-linking to CD8.

Fetal thymic organ cultures (FTOC) were tested as a model system to induce, in a polyclonal fashion, negative and positive thymic selection events. By flow cytometry, thymocytes developed in FTOC differed in several parameters from their in vivo differentiated counterparts. In particular, no clear distinction was possible between CD4+CD8+ immature cells with low TCR expression and mature CD4+ or CD8+ cells with high TCR expression. Thymocyte development in FTOC was manipulated with three different antibody reagents: anti-V beta 8 (F23.1), anti-Lyt-2.2 (19/178) and the quadroma derived bifunctional antibody HPHT-2, carrying one binding site of each. This antibody served also as a monovalent anti-V beta 8 reagent in FTOC from Lyt-2.1 mouse strains. Antibody 19/178 suppressed the development of single positive CD8+ cells, but only at very high concentrations. F23.1 and HPHT-2 suppressed the development of CD4+V beta 8+ and CD8+V beta 8+ thymocytes at relatively low concentrations giving rise to V beta 8 occupancies from about 2% upwards. Suppression was equally pronounced in cells with low and high TCR densities. Moreover, V beta 8 suppression occurred upon divalent and monovalent V beta 8 binding and was not significantly influenced by V beta 8-CD8 cross-linking. This suggests that ligation of the TCR alone is sufficient for clonal deletion. The data do not exclude a role for CD8 as an accessory adhesion molecule but suggest that exogenous cross-linking of CD8 to the TCR is not essential in transmembrane signaling for clonal deletion. At lower antibody concentrations giving rise to V beta 8 occupancies below detection, V beta 8-CD8 cross-linking by HPHT-2, but no divalent and monovalent V beta 8 ligation, induced an increase of CD8+V beta 8+ cells at the expense of CD4+ V beta 8+ cells with no change in the proportion of total V beta 8+ thymocytes. The latter effect was quantitatively of borderline significance but reproducible. These latter results are compatible with the hypothesis that cross-linking of the alpha beta TCR and CD8 on the thymocyte surface provides a maturation signal resulting in loss of CD4 from CD4+ CD8+ double positive immature thymocytes.

Animals↗

PubMed1990

Intact antigen receptor-mediated generation of inositol phosphates and increased intracellular calcium in CD4 CD8 T lymphocytes from MRL lpr mice.

The predominant T lymphocytes that accumulate in the peripheral lymphoid tissues of mice homozygous for the lpr gene bear the phenotype CD3+CD4-CD8-. By certain functional criteria these cells would appear to have impaired CD3-mediated signal transduction, in that they do not respond to alloantigen and produce little if any detectable IL-2 or other lymphokines. However, the signal pathway appears adequate for achieving other T cell functions, including induction of high affinity IL-2R, and thymic deletion. To clarify the basis of this seeming discrepancy, we examined transmembrane signal transduction in T cell subsets of lpr/lpr (lpr) and +/+ mice, as defined by increased [Ca2+]i and the generation of inositol phosphates (InsPs). Stimulation of lpr CD4-CD8- cells with anti-CD3 antibody produced prompt and sustained increases in the concentration of [C2+]i and in InsPs. Similar responses occurred in mature T cells from lpr and +/+ mice, except for the somewhat slower kinetics of their increased [Ca2+]i. In marked distinction to the anti-CD2-mediated response, Con A, even in high doses, could not stimulate any increase of [Ca2+]i in lpr CD4-CD8- cells, and only modest increases in InsPs. Mature T cells, whether of lpr or +/+ origin, yielded normal increased [Ca2+]i with Con A. The reason for the differences in signal transduction between anti-CD3 and Con A stimulation of lpr CD4-CD8- cells may relate to the absence of surface structures on these immature T cells that are required for activation by Con A but not by anti-CD3. The data demonstrate that the CD3 complex in lpr CD4-CD8- T cells can couple to phospholipase C to hydrolyze phosphoinositides. These activation properties of lpr CD4-CD8- T cells have interesting functional parallels to thymocytes at the time of thymic selection, as well as tolerance induction of mature T lymphocytes.

Animals↗