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PubMed2005

A novel role for CD28 in thymic selection: elimination of CD28/B7 interactions increases positive selection.

While the importance of the CD28/B7 costimulation pathway is well established for mature T cells, the role of CD28 in thymocyte selection is less well defined. The role of CD28 in both negative and positive selection was assessed using H-Y-specific TCR-transgenic (Tg) RAG-2-deficient (H-Yrag) mice. Negative selection in male H-Yrag mice was not affected by deficiency in CD28 or B7. Surprisingly, absence of CD28 or B7 in H-Yrag females resulted in increased numbers of CD8 single-positive (SP) thymocytes. The CD8 SP thymocytes found in these females were mature and functionally competent. Furthermore, double-positive (DP) thymocytes from CD28-knockout (CD28KO) or B7.1/B7.2 double-KO (B7DKO) females had higher levels of both CD5 and TCR than those from WT females, consistent with a stronger selecting signal. CD28KO H-Yrag fetal thymic organ cultures also had elevated numbers of thymic CD8 SP cells, reflecting increased thymic differentiation and not recirculation of peripheral T cells. Finally, increased selection of mature CD4 and CD8 SP T cells was observed in non-TCR-Tg CD28KO and B7DKO mice, indicating that this function of CD28-B7 interaction is not unique to a TCR-Tg model. Together these findings demonstrate a novel negative regulatory role for CD28 in inhibiting differentiation of SP thymocytes, probably through inhibition of thymic selection.

Animals↗
PubMed1995

A signal strength hypothesis of thymic selection: preliminary considerations.

During their differentiation, thymocytes are subjected to two rounds of selection. First, CD4-8- double-negative (DN) thymocytes with a functional TCR-beta chain express a alpha-beta+ CD3 complex on their surface and, as a consequence, are selected to mature to the CD4+8+ double-positive (DP) stage. This round ends after the initial proliferation of young DP thymocytes and is termed beta-chain selection. Second, DP thymocytes are selected on the basis of their alpha+beta+ CD3 complex. This is termed repertoire selection and the cells are given three choices: death by neglect selection, death by positive selection, or deletion by negative selection. Using anti-CD3 epsilon mAb as invariant ligand, signals for beta-chain selection of DN cells including proliferation of DP cells do not require a Ca2+ response, are independent of CD3 zeta, and are only slightly impaired in the absence of p56lck (lck). Signals that induce positive selection of DP thymocytes require a partial Ca2+ response and CD3 zeta but are independent of lck. Deletion of DP thymocytes requires a full-blown Ca2+ response and both, CD3 zeta and lck. Thymic selection thus appears to be governed by a gradient of signal intensities.

CD3 Complex↗
PubMed2006

Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection.

To elucidate the mechanisms of autoreactive T cell activation and expansion, we used endogenous viral superantigens (VSAg)-reactive T cells as a model of self-antigens in two strains of Foxp3-mutant mice. These two strains, together with wild-type mice, provided us with an advantage to simultaneously study the positively and negatively selected as well as rescued autoreactive T cells. We show here that while both VSAg-reactive and non-VSAg-reactive T cells are equally activated in Foxp3-mutant mice, only the VSAg-reactive T cells are preferentially expanded independently of their selected states in the thymus. The T cell activation appears to be controlled by Foxp3 through transcriptional regulation of early growth response (Egr) genes Egr-2 and Egr-3, and E3 ubiquitin (Ub) ligase genes Cblb, Itch and GRAIL, subsequently affecting degradation of two key signaling proteins, PLCgamma1 and PKC-theta. Physiologically, the positively, but not negatively selected VSAg-reactive T cells are spontaneously activated without significant expansion. The results suggest that autoreactive T cell activation is controlled by Foxp3 through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection.

Animals↗
PubMed1991

Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage.

Immature thymocytes, which coexpress CD4 and CD8, give rise to mature CD4+CD8- and CD4-CD8+ T cells. Only those T cells that recognize self-MHC are selected to mature, a process known as positive selection. The specificity of the T cell antigen receptor (TCR) for class I or class II MHC influences the commitment to a CD4 or CD8 lineage. This may occur by a directed mechanism or by stochastic commitment followed by a selection step that allows only CD8+, class I-specific and CD4+, class II-specific cells to survive. We have generated a mouse line expressing a CD8 transgene under the control of the T cell-specific CD2 regulatory sequences. Although constitutive CD8 expression does not affect thymic selection of CD4+ cells, selection of a class I-specific TCR in the CD8 subset is substantially improved. This outcome is consistent with a model for positive selection in which selection occurs at a developmental stage in which both CD4 and CD8 are expressed, and positive selection by class I MHC generates an instructive signal that directs differentiation to a CD8 lineage.

Animals↗
PubMed1990

Imprint of thymic selection on autoreactive repertoires.

We have focussed on the differences in origin and physiological properties of two classes of self-reactive T cells. Autoreactive T cells described in many laboratories are activated in the course of normal immune responses to foreign antigen. These T cells can be shown under well-defined conditions to be the direct progeny of antigen-stimulated precursors. This, together with evidence that their activation requirements can be distinguished from those of antigen-specific, MHC-restricted T cells, leads us to suggest that they represent a particular physiological state that recapitulates the conditions of thymic selection and is induced in many antigen-specific, MHC-restricted peripheral T cells as a result of normal antigen-dependent activation. Although it appears that the associated physiological properties can be stable in some in vitro maintained lines, it is possible that this is normally a transient state in vivo. Available evidence concerning the specificity of these T cells indicates only that they can be activated in the absence of any identifiable foreign antigen by class II MHC-syngeneic but not MHC-allogeneic stimulators. We have suggested that such T cells are specific for the same elements, possibly an association of MHC and other self-peptides (Singer et al. 1987), that are the basis for positive selection in the thymus. The properties of these autoreactive T cells need to be distinguished from those of T cells associated with autoimmune pathology. It is presumed that autoimmune T cells are directly activated in a resting state by specific self-peptides. Our interest in distinguishing these self-reactive T-cell populations has focussed on different predictions concerning the diversity of their associated self-reactive repertoires. The relative complexity of the immune repertoire expressed in autoreactive T cells expanded by positive selection and restimulated in the course of normal antigen-specific immune responses should be considerably greater than that of autoimmune T cells constrained by negative selection and a narrow window of escape from self-tolerance. We were greatly hindered in our initial efforts in this analysis by the considerable effort required to characterize any specific immune repertoire. A published technique employing poly(A) tailing (Frohman et al. 1988) did not work efficiently in our hands, although others (Loh et al. 1989) have apparently had some success. We describe above an alternative approach, linker-facilitated PCR, which we have employed for efficient repertoire analysis. Using this method we have been able to identify dominant utilization of the Va4 family in T cells specific for the synthetic peptide YYEELLKYYEELLK.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1996

Development of CD4-CD8- alpha beta TCR+NK1.1+ T lymphocytes: thymic selection by self antigen.

Development of CD4-CD8- double negative (DN) alpha beta TCR+ cells were examined by cell transfer experiments using an Ly-5 congenic mouse system. Purified DN alpha beta TCR+ thymocytes injected intrathymically emigrated from the thymus to the spleen. The same cells did not return to the thymus when injected i.v. Similarly, peripheral DN alpha beta TCR+ cells from spleen and liver did not go to the thymus when injected i.v. but migrated to the spleen. These results indicate that DN alpha beta TCR+ thymocytes develop within the thymus and emigrate to peripheral organs. It is thus likely that peripheral DN alpha beta TCR+ cells are at least partly of thymic origin. DN alpha beta TCR+ thymocytes are unique in that they express a natural killer cell marker, NK1.1, which is not found on conventional T cells. We further examined the thymic selection of DN alpha beta TCR+NK1.1+ thymocytes by using an anti-HY TCR-transgenic (tg)/Rag-2(-/-) mouse system with H-2 backgrounds that were negative, positive, or nonselecting for conventional T cells. The number of DNtg TCR alpha beta+NK1.1+ cells was m prominent in male H-2b animals in which conventional T cells are deleted by HY/H-2Db recognition. Fewer DNtg TCR alpha beta+NK1.1+ cells were found in H-2b females (positive selecting background), and almost no DNtg TCR alpha beta+NK1.1+ cells were detected in H-2d animals (nonselecting background). Unlike conventional T cells, DNtg TCR alpha beta+NK1.1+ cells from anti-HY/Rag-2(-/-) H-2b mice express Fc(epsilon)RI(gamma) and CD3zeta as DN alpha beta TCR+NK1.1+ cells from normal C57BL/6 mice. Our results indicate that DNtg TCR alpha beta+NK1.1+ cells are positively selected by self Ag/MHC and emigrate to the peripheral organs.

Adoptive Transfer↗
PubMed1974

Selective thymic localization of murine leukemia virus-related antigens in C57BL-Ka mice after inoculation with radiation virus.

The tissue distribution and extent of virus-specific antigen expression were studied by immunofluorescence as a function of time and of lymphoma development in adult C57BL/Ka (Fv-1(b)) mice after intravenous injection of radiation leukemia virus, a B-tropic murine leukemia virus. Viral antigens were detected earlier in the thymus (1 week) than in the bone marrow, spleen, or lymph nodes (2-3 weeks). Despite an initial virus-induced thymic involution, the percentage of immunofluorescence-positive cells in the thymus rapidly increased thereafter to 65-80%, at which level it remained until 9 weeks, at which time increases in size and weight, histological changes, and an increased number of blastoid cells indicated the onset of lymphoma development in the thymus. In contrast, the percentage of immunofluorescence-positive cells in the bone marrow, spleen, and nodes remained low, and gradually decreased to zero within 8 weeks after thymectomy. The selective thymic localization of antigens induced by radiation leukemia virus in C57BL/Ka mice is in striking contrast to the previously reported ubiquitous tissue distribution of the Gross-AKR virus, an N-tropic virus, in its natural host, the Fv-1(n), AKR strain with a high incidence of leukemia.

Animals↗
PubMed1999

Differential CD4/CD8 subset-specific expression of highly homologous rat Tcrb-V8 family members suggests a role of CDR2 and/or CDR4 (HV4) in MHC class-specific thymic selection.

Different rat Tcrb haplotypes express either TCR beta variable segment (Tcrb-V) 8.2l or 8.4a. Both V segments bind the mAb R78 but differ by one conservative substitution (L14V) and clusters of two and four substitutions in the complementarity-determining region (CDR) 2 and CDR4 [hypervariable loop 4 (HV4)]. Independently of MHC alleles numbers of R78+ CD4+ cells are lower in Tcrb-V8.2l-expressing than in Tcrb-V8.4a-expressing strains. Expression of R78+ TCR during T cell development, analysis of backcross populations and generation of a Tcrb congenic strain [LEW.TCRB(AS)] define two mechanisms how Tcrb haplotypes affect the frequency of R78+ cells, one acting prior to thymic selection leading to up to 2-fold higher frequency of Tcrb-V8.4a versus Tcrb-V8.2l in unselected thymocytes and another occurring between the TCRlow and the CD4/CD8 single-positive stage. The latter leads to a 50% reduction of frequency of Tcrb-V8.4a CD8+ cells but not CD4+ cells and does not affect either subset of Tcrb-V8.2l cells. A comparison of rat classical class I MHC (RT1.A) sequences and current models of TCR-MHC-peptide interaction suggests that this reduction in frequency of Tcrb-V8.4a CD8 cells may be a consequence of differential selection of Tcrb-V8.2l versus Tcrb-V8.4a TCR by differential binding of CDR2beta to highly conserved areas of C-terminal parts of the alpha helices of class I MHC molecules.

Alleles↗
PubMed1990

Expression of identical V alpha V beta gene pairs by IE-alloreactive and IE-restricted, antigen-specific T cells from MHC disparate mice. Evidence for thymic selection of V(D)J combinations.

Alloreactive T cell hybridomas specific for IEk and/or IEb MHC Ag were obtained from IE-nonexpressor (IE alpha b) mice. The TCR V alpha and V beta gene segments used were identified by Northern blot and RNase protection. A large proportion (24 of 80 hybridomas tested) employed the same V alpha genes (V alpha 11.1 or V alpha 11.2) as are utilized in the IEk and IEb restricted response to the Ag cytochrome c. Of these 24 alloreactive hybridomas, 10 also expressed V beta genes utilized in the IE plus cytochrome c repertoire. Structural similarity between the two related sets of TCR indicates that V alpha segments can play a determining role in MHC specificity. These data also suggest that thymic selection based on TCR reactivity with self-MHC products acts on particular V(D)J combinations rather than on V alpha V beta pairings alone.

Animals↗
PubMed1999

Thymic selection by a single MHC/peptide ligand: autoreactive T cells are low-affinity cells.

In H2-M- mice, the presence of a single peptide, CLIP, bound to MHC class II molecules generates a diverse repertoire of CD4+ cells. In these mice, typical self-peptides are not bound to class II molecules, with the result that a very high proportion of H2-M- CD4+ cells are responsive to the various peptides displayed on normal MHC-compatible APC. We show here, however, that such "self" reactivity is controlled by low-affinity CD4+ cells. These cells give spectacularly high proliferative responses but are virtually unreactive in certain other assays, e.g., skin graft rejection; responses to MHC alloantigens, by contrast, are intense in all assays. Possible explanations for why thymic selection directed to a single peptide curtails self specificity without affecting alloreactivity are discussed.

Adoptive Transfer↗
PubMed1988

Thymic selection of H-2-incompatible bone marrow cells in SCID mice. Differences in T help for induction of B cell IgG responses versus cytotoxic T cells.

Mice with congenital severe combined immunodeficiency disease (SCID) failed to mount either a T cell-independent IgM or T cell-dependent IgG anti-vesicular stomatitis virus (VSV) Indiana (IND) response. They did not generate cytotoxic T cells against lymphocytic choriomeningitis virus (LCMV) or vaccinia virus, but exhibited NK cell-like activities. When SCID mice were given bone marrow from syngeneic BALB/c (H-2d) nu/nu mice, all immune responses were expressed at control levels. If SCID mice were reconstituted with allogeneic H-2b C57BL/6 nu/nu bone marrow, the following primary anti-viral immune responses were measured. T-independent IgM anti-VSV-IND were normal, but T-dependent IgG anti-VSV-IND responses were absent. Cytotoxic T cell responses to LCMV and vaccinia virus were within normal ranges, were donor cell mediated, and were specific exclusively for the recipient SCID H-2d type. Since antigen presentation by spleen cells was functional in these chimaeras, the presented results indicate that (a) thymic selection of T cell restriction is strict; and (b) the type of T help necessary for B cells depends upon H-2-restricted contact between T and B cells, whereas, such contact-dependent help is not mandatory for the induction of virus-specific cytotoxic T cells.

Animals↗
PubMed1992

Activation events during thymic selection.

During their differentiation in the mouse thymus, CD4+8- cells undergo several of the sequential changes observed upon normal activation of mature, peripheral CD4+ lymphocytes. Expression of CD69, an early activation marker, is first observed on a minority of cells at the T cell receptor (TCR)lo/med double-positive stage, is maximal (50-90%) on heat-stable antigen (HSA)hi TCRhi double-positive, HSAhi TCRmed CD4+8lo, and HSAhi TCRhi CD4+8- cells, and is downmodulated at the mature HSAlo CD4+8- stage. In contrast, CD44, a late activation marker, is selectively expressed at the HSAlo stage. The set of lymphokines that CD4+8- thymocytes can produce upon stimulation also characteristically expands from mainly interleukin 2 (IL-2) at the HSAhi stage, to IL-2 and very large amounts of IL-4, IL-5, IL-10, and interferon gamma (IFN-gamma) at the HSAlo stage. 1 in 30 HSAlo CD4+8- adult thymocytes secrete IL-4 upon stimulation through their TCR. This frequency is 25% of the frequency of IL-2 producers, about 100-fold above that of peripheral (mainly resting) CD4+ T cells. With time after their generation in organ culture, CD4+8- thymocytes lose their capacity to secrete IL-4, IL-5, and IFN-gamma, but not IL-2. Similarly, the frequency of IL-4, but not of IL-2, producers progressively decreases after emigration to the periphery as judged by direct comparison between thymic and splenic CD4+ cells in newborns, or by following the fate of intrathymically labeled CD4+8- cells in adults after their migration to the spleen. This sequence suggests that thymic selection results from an activation process rather than a simple rescue from death at the double-positive stage, and shows that the functional changes induced after intrathymic activation, although transient, are still evident after export to the periphery.

Animals↗
PubMed2000

Thymic selection is influenced by subtle structural variation involving the p4 residue of an MHC class I-bound peptide.

The T lineage repertoire is shaped by opposing processes of positive and negative selection. To probe the specificity of selection, N15 TCR-transgenic (tg) recombinase-activating gene (RAG)-2(- / -) H-2(b) mice recognizing the VSV8 octapeptide RGYVYQGL bound to K(b) were utilized in conjunction with VSV8 variants differing only at the central p4 position. The V4I mutant octamer, like VSV8, induces negative selection of immature double-positive thymocytes on the beta(2)-microglobulin (beta(2)M)(+ / +) background and is a strong agonist for mature N15 T cells. In contrast, V4L or V4norvaline octamers promote positive selection in N15tg RAG-2(-/-) beta(2)M(-/-) H-2(b) fetal thymic organ culture and are weak agonists for N15 T cells. Hence, the absence of a p4 side chain Cbeta-methyl group results in positive selection of the N15 TCR. Hydrophobicity of the p4 residues also modulates thymocyte fate: the positively selecting norvaline and leucine variants have one and two Cgamma-methyl groups, respectively, while the weakly selecting gamma-methylleucine p4 contains three Cgamma-methyl groups. Moreover, the most hydrophobic octamer containing p4 cyclohexylglycine substitution fails to select. Thus, for N15 and presumably other MHC class I-restricted TCR, there is a high degree of structural specificity to peptide-dependent thymic selection processes.

Animals↗
PubMed2002

Peptide specificity of thymic selection of CD4+CD25+ T cells.

The CD4(+)CD25(+) regulatory T cells can be found in the thymus, but their need to undergo positive and negative selection has been questioned. Instead, it has been hypothesized that CD4(+)CD25(+) cells mature following TCR binding to MHC backbone, to low abundant MHC/peptide complexes, or to class II MHC loaded with peripheral autoantigens. In all these circumstances, processes that are distinct from positive and negative selection would govern the provenance of CD4(+)CD25(+) cells in the thymus. By comparing the development of CD4(+)CD25(-) and CD4(+)CD25(+) cells in mice expressing class II MHC molecules bound with one or many peptide(s), we show that the CD4(+)CD25(+) cells appear during natural selection of CD4(+) T cells. The proportion of CD4(+)CD25(+) cells in the population of CD4(+) thymocytes remains constant, and their total number reflects the complexity of selecting class II MHC/peptide complexes. Hence, thymic development of CD4(+)CD25(+) cells does not exclusively depend on the low-density, high-affinity MHC/peptide complexes or thymic presentation of peripheral self-Ags, but, rather, these cells are selected as a portion of the natural repertoire of CD4(+) T cells. Furthermore, while resistant to deletion mediated by endogenous superantigen(s), these cells were negatively selected on class II MHC/peptide complexes. We postulate that while the CD4(+)CD25(+) thymocytes are first detectable in the thymic medulla, their functional commitment occurs in the thymic cortex.

Animals↗
PubMed2001

Post-thymic selection of peripheral CD4+ T-lymphocytes on class II major histocompatibility antigen-bearing cells.

Following positive and negative selection in the thymus, mature CD4+ T-cells emigrate into peripheral lymphoid organs. Whether resting T-cells require periodic stimulation to remain viable in the absence of antigen is important for understanding peripheral T-cell homeostasis. A prerequisite for T-cell receptor (TCR)-mediated signals in maintaining peripheral CD4+ T-cell longevity has been demonstrated. Here, we show in mice expressing a mutant I-Abeta transgene on an I-Abeta knockout background that naïve CD4+ T-cells also require engagement of their CD4 coreceptors by peripheral, class II MHC-bearing cells for their survival. The transgene's product combines with endogenous Aalpha, but this mutant AalphaAbeta heterodimer cannot interact with CD4 molecules, although it efficiently presents antigens to TCRs. Resting CD4+ T-lymphocytes from mutant Abeta transgenic mice die by apoptosis at a much higher rate than do CD4+ T-cells from normal mice. Apoptosis of CD4+ T-cells in mutant Abeta transgenic mice is partially mediated by Fas. Adoptive transfer experiments revealed that the increase in apoptosis is due to a lack of interactions with mutant MHC class II rather than to an intrinsic defect in the CD4+ T-cells selected on mutant Abeta-expressing thymic epithelial cells. Thus, interactions between CD4 and MHC class II molecules contribute to the regulation of homeostasis in the peripheral immune system. Our results further suggest that thymic emigrant cells are continuously retested in the periphery for appropriate coreceptor interactions. Peripheral selection may be important in eliminating potentially autoreactive T-cells.

Animals↗
PubMed2003

Altered positive selection due to corecognition of floppy peptide/MHC II conformers supports an integrative model of thymic selection.

Thymocytes bearing the E alpha 52-68/I-A(b) complex-specific 1H3.1 alpha beta T cell antigen receptor are positively selected in Ab-Ep [Ab-Ep transgenic, invariant chain (Ii)(-/-), I-A beta(b-/-)] mice, where I-A(b) molecules present only E alpha 52-68. Although Ii reintroduction led to deletion, I-A beta(b) reintroduction disrupted positive selection. T cell antigen receptor transgenic Ab-Ep I-A beta(b+) mice had a large thymus with an increased absolute number of CD4(+)CD8(+) cells and no overt signs of deletion. Unlike Ab-Ep Ii(+) antigen-presenting cells, Ab-Ep I-A beta(b+) antigen-presenting cells did not activate 1H3.1 T cells. However, their capacity to present E alpha 52-68 was intact. Thus, positive selection of 1H3.1 thymocytes on the tight compact E alpha 52-68/I-A(b) complex is neutralized by the corecognition of loose compact self-peptide/I-A(b) conformers that do not interfere with the cognate activation of mature 1H3.1 T cells. The data support the notion that the integration of distinct signals generated by the simultaneous recognition of multiple self-peptide/MHC complexes directs intrathymic selection of T cells.

Animals↗
PubMed1992

Altered thymocyte development resulting from expressing a deleting ligand on selecting thymic epithelium.

The maturation of CD4+8- and CD4-8+ thymocytes from CD4+8+ thymocytes is dependent on the mandatory interaction of their alpha beta TCR with selecting ligands expressed on thymic epithelial cells (TE). This is referred to as positive selection. The deletion of CD4+8+ thymocytes that express autospecific TCR (negative selection) is mediated primarily by bone marrow-derived cells. Previous studies have shown that TE is relatively ineffective in mediating the deletion of CD4+8- thymocytes expressing autospecific TCR but TE can render them anergic, i.e., nonresponsive, to the self Ag. The mechanism by which anergy is induced in these cells is unknown. In this study, we used thymocytes expressing a transgenic TCR specific for the male Ag presented by H-2Db class I MHC molecules to examine how expression of the deleting ligand by TE affects thymocyte development and phenotype. The development of female TCR-transgenic thymocytes was examined in irradiated male hosts or in female hosts that had received male fetal thymic epithelial implants. It was observed that the development of transgenic-TCR+ thymocytes was affected in mice with male TE. CD4+8+ thymocytes with reduced CD8 expression and markedly enhanced transgenic TCR expression accumulated in mice with male TE. Development of CD4-8+ thymocytes was also affected in these mice in that fewer were present and they expressed an intermediate CD8 coreceptor level. These CD4-8+ thymocytes expressed a high level of the transgenic TCR, retained the ability to respond to anti-TCR antibodies, but were nonresponsive to male APC. However, the maturation of CD4+8- thymocytes, which are also derived from CD4+8+ precursor cells, was relatively unaffected. In an in vitro assay for assessing negative selection, male TE failed to delete CD4+8+ thymocytes expressing the transgenic TCR under conditions where they were efficiently deleted by male dendritic cells. Collectively these results support the conclusion that male TE was inefficient in mediating deletion. Furthermore, expression of the deleting ligand on thymic epithelium interferes with the maturation of functional male-specific T cells and results in the accumulation of CD4+8+ and CD4-8+ thymocytes expressing a lower level of the CD8 coreceptor but a high level of the transgenic TCR.

Animals↗