Divergent Changes in the Sensitivity of Maturing T Cells to Structurally Related Ligands Underlies Formation of a Useful T Cell Repertoire (original) (raw)
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International Immunology, 2000
Experiments with synthetic antigen peptides have suggested that a critical parameter that determines the developmental fate of an immature thymocyte is the affinity of interaction between TCR and self-peptide/MHC expressed on thymic stromal cells. To test the physiological relevance of this model for thymocyte development, we determined the affinity of the anti-HY TCR (B6.2.16) expressed on CD8 ⍣ cells for thymic self-peptide/H-2D b tetramers, then examined the ability of these self-peptides to determine the outcome of B6.2.16 CD8 cell selection in the thymus. The B6.2.16 TCR bound the male HY self-antigen with high affinity. Thymic self-peptides, which are highly abundant on the surface of thymic epithelial cells, bound the B6.2.16 TCR with low affinity. The ability of self-peptides to trigger positive or negative selection of B6.2.16 CD8 cells in cultured fetal thymi was determined by the relative affinity of self-peptide/H-2D b for the B6.2.16 TCR. Highaffinity binding of the HY self-peptide resulted in B6.2.16 TCR complex ζ chain phosphorylation and the negative selection of B6.2.16 CD8 cells. Low-affinity binding of thymic self-peptides to B6.2.16 TCR resulted in the positive selection of B6.2.16 CD8 cells. Differences between the binding affinities of self-peptides to B6.2.16 TCR accounted for the self-peptide specificity of B6.2.16 CD8 cell positive selection. We conclude that the relative affinity of TCR for thymic selfpeptide/class I MHC is a critical parameter in determining fate of CD8 ⍣ cells during thymic selection.
Immunity, 1999
tive transfer experiments with CD8 ϩ cells from MHC class I (H2-D b )-reactive HY TCR transgenic mice showed that CD8 ϩ cells survived well in H2-D bϩ hosts but disappeared rapidly in H2-D bϪ mice. The above findings imply that survival of mature naive CD4 ϩ and CD8 ϩ T cells requires continuous, albeit covert, signaling through the TCR. In support of this idea, Summary T cells deficient in a Kruppel-like zinc finger transcription factor designated lung Kruppel-like factor (LKLF) were Positive selection to self-MHC/peptide complexes has found to have a very short life span (Kuo et al., 1997). long been viewed as a device for skewing the T cell Interestingly, LKLF Ϫ embryonic stem cells led to normal repertoire toward recognition of foreign peptides pre-T cell development in the thymus but to the appearance sented by self-MHC molecules. Here, we provide eviof only a few mature T cells in the periphery, because dence for an alternative possibility, namely, that the the T cells underwent spontaneous activation and died self-peptides controlling positive selection in the thyrapidly from Fas-mediated apoptosis. LKLF thus apmus serve to maintain the longevity of mature T cells pears to be involved in translating the low-level TCR in the periphery. Surprisingly, when total T cell numsignaling received from contact with self-MHC molebers are reduced, these self-ligands become overtly cules into signals for mature T cells to persist in the stimulatory and cause naive T cells to proliferate and quiescent state. undergo homeostatic expansion.
Stage-dependent reactivity of thymocytes to self-peptide–MHC complexes
Proceedings of the National Academy of Sciences, 2007
In mice that express a transgene for the 2C T cell antigen-receptor (TCR) and lack a recombinase-activating gene (2C + RAG −/− mice) most of the peripheral T cells are CD8 + , a few are CD4 + , and a significant fraction are CD4 − CD8 − [double negative (DN)]. The DN 2C cells, like DN T cells that are abundant in various other αβ TCR-transgenic mice, appear to be derived directly from DN thymocytes that prematurely express the TCR transgene. The DN 2C cells are virtually absent in mice deficient in major histocompatibility complex class II (MHC-II) but more abundant in mice deficient in MHC-I, suggesting that the DN 2C thymocytes are positively selected by self-peptide–MHC-II (pMHC-II) complexes and negatively selected by self-pMHC-I complexes. The pMHC-I complexes, however, positively select CD8 + 2C T cells in the same mice. The different effects of thymic pMHC-I on DN and CD8 + thymocytes are consistent with the finding that DN 2C thymocytes are more sensitive than more mature CD...
Preselection Thymocytes Are More Sensitive to T Cell Receptor Stimulation Than Mature T Cells
Journal of Experimental Medicine, 1998
During T cell development, thymocytes which are tolerant to self-peptides but reactive to foreign peptides are selected. The current model for thymocyte selection proposes that self-peptide-major histocompatibility complex (MHC) complexes that bind the T cell receptor with low affinity will promote positive selection while those with high affinity will result in negative selection. Upon thymocyte maturation, such low affinity self-peptide-MHC ligands no longer provoke a response, but foreign peptides can incidentally be high affinity ligands and can therefore stimulate T cells. For this model to work, thymocytes must be more sensitive to ligand than mature T cells. Contrary to this expectation, several groups have shown that thymocytes are less responsive than mature T cells to anti-T cell receptor for antigen (TCR)/CD3 mAb stimulation. Additionally, the lower TCR levels on thymocytes, compared with T cells, would potentially correlate with decreased thymocyte sensitivity. Here we compared preselection thymocytes and mature T cells for early activation events in response to peptide-MHC ligands. Remarkably, the preselection thymocytes were more responsive than mature T cells when stimulated with low affinity peptide variants, while both populations responded equally well to the antigenic peptide. This directly demonstrates the increased sensitivity of thymocytes compared with T cells for TCR engagement by peptide-MHC complexes.
2010
The differentiation of intestinal intraepithelial lymphocytes (IEL) remains controversial, which may be due in part to the phenotypic complexity of these T cells. We have investigated here the development of IEL in mice on the recombination activating gene (RAG)-2 Ϫ / Ϫ background which express a T cell antigen receptor (TCR) transgene specific for an H-Y peptide presented by D b (H-Y/D b ϫ RAG-2 Ϫ mice). In contrast to the thymus, the small intestine in female H-Y/D b ϫ RAG-2 Ϫ mice is severely deficient in the number of IEL; TCR transgene ϩ CD8 ␣␣ and CD8 ␣ are virtually absent. This is similar to the number and phenotype of IEL in transgenic mice that do not express the D b class I molecule, and which therefore fail positive selection. Paradoxically, in male mice, the small intestine contains large numbers of TCR ϩ IEL that express high levels of CD8 ␣␣ homodimers. The IEL isolated from male mice are functional, as they respond upon TCR cross-linking, although they are not autoreactive to stimulator cells from male mice. We hypothesize that the H-Y/D b TCR fails to undergo selection in IEL of female mice due to the reduced avidity of the TCR for major histocompatibility complex peptide in conjunction with the CD8 ␣␣ homodimers expressed by many cells in this lineage. By contrast, this reduced TCR/CD8 ␣␣ avidity may permit positive rather than negative selection of this TCR in male mice. Therefore, the data presented provide conclusive evidence that a TCR which is positively selected in the thymus will not necessarily be selected in IEL, and furthermore, that the expression of a distinct CD8 isoform by IEL may be a critical determinant of the differential pattern of selection of these T cells.