The Cytoplasmic Domain of CD4 Promotes the Development of CD4 Lineage T Cells (original) (raw)
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European Journal of Immunology, 1994
We have characterized a prominent (15-20 % ) thymocyte population expressing CD4 at a high and CD8 at a low level (CD4+81°) in mice transgenic for a T cell receptor (TCR) restricted by major histocompatibility complex (MHC) class I molecules. The results demonstrate that the CD4+S1" population is an intermediate stage between immature CD4+8+ and end-stage CD4+8-thymocytes and that the survival of these cells crucially depends on the successful interaction of the transgenicTCR with self MHC class I molecules. In addition we demonstrate that the avidity of the interaction betweenTCR and self MHC class I molecules determines whether CD4+8I0 thymocytes are found in significant numbers in this transgenic model. Our findings support a selective and multi-step model of T cell differentiation in the thymus.
Proceedings of the National Academy of Sciences, 2006
Differences in T cell receptor (TCR) signaling initiated by interactions among TCRs, coreceptors, and self-peptide–MHC complexes determine the outcome of CD4 versus CD8 lineage of T cell differentiation. The H-2L d and K bm3 alloreactive 2C TCR is positively selected by MHC class I K b and a yet-to-be identified nonclassical class I molecule to differentiate into CD8 + T cells. Here we describe two mechanisms by which CD4 + 2C T cells can be generated in 2C TCR-transgenic mice. In the RAG −/− background, development of CD4 + 2C T cells requires the expression of both I-A b and the TAP genes, indicating that both MHC class I and II molecules are required for positive selection of these T cells. Notably, only some of the 2C + RAG −/− mice (≈30%) develop CD4 + 2C T cells, with frequencies in individual mice varying from 0.5% to as high as ≈50%. In the RAG + background, where endogenous TCRα genes are rearranged and expressed, CD4 + 2C T cells are generated because these cells express t...
MHC class I is required for peripheral accumulation of CD8+ thymic emigrants
Journal of immunology (Baltimore, Md. : 1950), 1998
MHC molecules influence the fate of T lymphocytes at two important stages of their differentiation. Recognition of self peptide/MHC complexes in the thymus determines whether immature T cells should live and mature into immunocompetent T cells or whether they should die. In the periphery, recognition of Ags presented by MHC molecules induces T cell activation, proliferation, and differentiation into effector/memory T cells. We describe in this work a third role that MHC molecules play in T cell physiology. CD8+ thymic emigrants require presence of MHC class I molecules in the periphery to seed the peripheral lymphoid organs. Numbers of CD8+ T cells are reduced severely in both the thymus and the periphery of beta2-microglobulin-deficient (beta2m[-/-]) mice. When grafted with wild-type (beta2m[+/+]) thymic epithelium, immature beta2m(-/-) T cells that populate the graft develop into functional mature CD8+ cells. However, significant numbers of peripheral CD8+ cells in grafted beta2m(...
Immunity, 1996
atrophies after puberty and plays little role in the mainte-and Takeyuki Shimizu* nance of the T cell pool in secondary lymphoid organs *Basel Institute for Immunology (Sprent, 1993). In fact, the turnover of mature T cells is Grenzacherstrasse 487 not detectably affected by adult thymectomy (Tough CH-4005 Basel and Sprent, 1994), and a peripheral T cell pool is main-Switzerland tained in a self-renewing manner by cell division and † F. Hoffmann-La Roche Ltd. cell death. Naive T cells, which have not encountered CH-4070 Basel antigens, can survive for prolonged periods and are able Switzerland to mount primary responses to new antigens in advanced age (Bruno et al., 1995). In addition, TCR V␣ and V usages of CD4 ϩ T cells do not change with age, Summary suggesting that the TCR repertoire of CD4 ϩ T cells remains constant with age (Callahan et al., 1993). Since We grafted fetal thymi from wild-type mice into immuthe total number of cells in lymphoid organs is relatively nodeficient RAG-2 Ϫ/Ϫ or class II Ϫ/Ϫ RAG-2 Ϫ/Ϫ (class II constant, dividing T cell clones would dilute out resting MHC Ϫ) recipients and followed the fate of naive CD4 ؉ T cell clones. It is thus surprising that enormous diversity T cells derived from the grafts. In both types of recipiof the TCR repertoire is maintained for extended peents, newly generated CD4 ؉ T cells proliferated to the riods. same extent in the periphery and rapidly filled the It is not clear whether T cells can divide in vivo without empty T cell compartment. However, CD4 ؉ T cells in signaling through the TCR. The activation of mature class II Ϫ recipients gradually decreased in number over CD4 ϩ T cells in vivo generally results from the binding 6 months. These results show that interactions beof the TCR to specific immunogenic peptides embedded tween the TCR and class II molecules are not required in MHC class II molecules, which are expressed mainly for newly generated CD4 ؉ T cells to survive and prolifon professional antigen-presenting cells in the peripherate, but are necessary to maintain the size of the ery. Similarly, it is believed that TCR-mediated signals peripheral T cell pool for extended periods. are required for the proliferation of T cell clones in vitro. However, the following observations suggest that sig
International Immunology, 1999
Different rat Tcrb haplotypes express either TCR β variable segment (Tcrb-V) 8.2 l or 8.4 a . 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-V8.2 lexpressing than in Tcrb-V8.4 a -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-V8.4 a versus Tcrb-V8.2 l in unselected thymocytes and another occurring between the TCR low and the CD4/CD8 single-positive stage. The latter leads to a 50% reduction of frequency of Tcrb-V8.4 a CD8 ⍣ cells but not CD4 ⍣ cells and does not affect either subset of Tcrb-V8.2 l 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-V8.4 a CD8 cells may be a consequence of differential selection of Tcrb-V8.2 l versus Tcrb-V8.4 a TCR by differential binding of CDR2β to highly conserved areas of C-terminal parts of the α helices of class I MHC molecules. selection) to mature T cells requires TCR-MHC-peptide interaction of appropriate strength (either affinity or avidity) while lack of such binding results in 'death by negligence or ignorance'. Thymocytes with potentially autoreactive TCR of high affinity for self molecules are deleted by induction of apoptosis (negative selection) (3-5). At the level of thymocyte populations, selection by MHC starts with cortical thymocytes expressing low levels of TCR but high levels of both CD4 and CD8, and ends with medullary thymocytes which express either CD4 or CD8 and high levels of TCR. Consequently, differences in V segment usage between these immature by guest on February 23, 2016 http://intimm.oxfordjournals.org/
Functional CD8 + but not CD4 + T cell responses develop independent of thymic epithelial MHC
Proceedings of the National Academy of Sciences, 2006
The role of nonthymic epithelial (non-TE) MHC in T cell repertoire selection remains controversial. To analyze the relative roles of thymic epithelial (TE) and non-TE MHC in T cell repertoire selection, we have generated tetraparental aggregation chimeras (B6-nude↔BALB/c and B6↔BALB/c-nude) harboring T and B cells from both parents, whereas TE cells originated exclusively from the non-nude donor. These chimeras mounted protective virus-specific TE and non-TE MHC-restricted T cell responses. To further evaluate whether non-TE MHC alone was sufficient to generate a functional T cell repertoire, we generated tetraparental aggregation chimeras lacking MHC class II (B6-nude↔MHCII −/− ) or both MHC molecules (B6-nude↔MHCI −/− II −/− ) on TE cells, but not on cells of B6-nude origin. Chimeras with MHC-deficient TE cells mounted functional virus-specific CD8 + but not CD4 + T cell responses. Thus, maturation of functional CD4 + T cell responses required MHC class II on thymic epithelium, wh...
The influence of the thymic environment on the CD4-versus-CD8 T lineage decision
Nature Immunology, 2003
T cell receptor signaling is an essential factor regulating thymocyte selection, but the function of the thymic environment in this process is not clear. In mice transgenic for major histocompatibility complex class II-restricted T cell receptors, every thymocyte is potentially selectable for maturation in the CD4 lineage. To address whether selection frequency affects positive selection, we created hematopoietic chimeras with mixtures of selectable and nonselectable precursors. With increased proportions of nonselectable thymocytes, positive selection of MHC class II-specific precursors was enhanced, generating not only CD4 but also CD8 thymocytes. These results indicate that the CD4 versus CD8 fate of selectable precursors can be influenced by the selection potential of its neighbors.
The Journal of experimental medicine, 1994
Although mature CD4+ T cells bear T cell receptors (TCRs) that recognize class II major histocompatibility complex (MHC) and mature CD8+ T cells bear TCRs that recognize class I MHC, it is possible that the initial commitment of an immature thymocyte to a CD4 or CD8 lineage is made without regard to the specificity of the TCR. According to this model, CD4+ cells with class I TCR do not mature because the CD8 coreceptor is required for class I MHC recognition and positive selection. If this model is correct, constitutive expression of CD8 should allow CD4+ T cells with class I-specific TCRs to develop. In this report, we show that mature peripheral CD4+ cells are present in class II MHC-deficient mice that express a constitutive CD8.1 transgene. These cells share a number of properties with the major class II MHC-selected CD4 population, including the ability to express CD40 ligand upon activation. Although mature CD4 cells are also detectable in the thymus of class II MHC mutant/CD8...
Molecular Immunology, 1998
CD4 contributes to antigen recognition of T cells by binding to class II MHC molecules. There is heterogeneity in expression of CD4 coreceptor among CD4+CD8+ thymocytes. We have investigated whether the expression level of coreceptor influences positive selection. Thymocytes of mice expressing transgenic ,?2"5-Ig-light-chain/I-Ed specific TCR are poorly positively selected because they fail to allelically exclude endogenous TCR r chain genes and because there is no skewing towards CD4. Transient overexpression of CD4 during thymocyte development, in mice transgenic for both TCR and CD4, resulted in skewing towards CD4 in the periphery, reduced rearrangement and expression of endogenous z-chains, and decreased levels of thymocyte RAG-I transcripts. Kinetic BrdU labeling experiments showed that single CD4+ thymocytes developed faster, representing the predominant population even in the cortex of the double transgenic thymi. These results demonstrate that increased coreceptor expression can compensate for poorly selectable TCR, supporting avidity and instructional models for positive selection of thymocytes. :Q