Programming for cytotoxic effector function occurs concomitantly with CD4 extinction during CD8+ T cell differentiation in the thymus (original) (raw)
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Responsiveness of fetal and adult CD4-, CD8- thymocytes to T cell activation
The Journal of Immunology
Day-14 fetal CD4-, CD8- thymocytes showed a greater proliferative response to PMA + IL-4 than did adult double-negative thymocytes. In contrast, adult double-negative thymocytes were more responsive to PMA + IL-1 + IL-2 or to IL-1 + IL-2 alone. The adult double-negative thymocytes showed significantly greater proliferation than fetal thymocytes after stimulation via anti-CD3 or anti-Thy-1 in the presence or absence of interleukins (IL-1 + IL-2 or IL-4). Adult CD4-, CD8- thymocytes also exhibited greater calcium mobilization following anti-CD3 stimulation IL-2-dependent activation with anti-Thy-1 or IL-1 + IL-2 in the absence of PMA resulted in marked expansion of CD 3+, F23.1+, CD4-, CD8- thymocytes, a population absent in fetal thymocytes but constituting 4% of pre-cultured CD4-, CD8- adult thymocytes. IL-4 + PMA failed to expand this CD 3+ population. It is hypothesized that before expression of functional TCR, T cell development may be more dependent on activation pathways not us...
European Journal of Immunology, 1994
We have studied the differentiation and repertoire selection during the maturation of CD4+CD8+ (DP) thymocytes into CD4+CD8-(CD4SP) and CD8+CD4-(CD8SP) T cells, in normal mice, mice transgenic for T cell receptor (TcR)-ap restricted by either class I or class I1 major histocompatibility (MHC), and in mice deficient in class I or class I1 MHC expression. Our data suggest that mature CD4 and CD8 Tcells derive from different pathways of Tcell differentiation in the thymus. Thus, interaction of DP thymocytes with MHC class I1 leads to the immediate down-regulation of CD8, which occurs simultaneously with an increase inTcR expression; DPTcRIOHSAhi thymocytes mature into a CD4+CD8I0 TcRhiHSAhi intermediate population. This cell population generates CD4SP thymocytes, the majority of which are still HSAhi. In contrast, interaction with MHC class I induces the up-regulation of TcR, which precedes the downregulation of CD4; DPTcRIO generate DPTcRhi thymocytes, the majority of which are the committed precursors of CD8SP cells. Further differentiation results in CD4 down-regulation and the transition from DPTcRhl into CD8+CD4I0 TcRhiHSAIO and CD8SPTcRhiHSA-T cells. Since down-regulation of CD4 and CD8 occurs at different stages of thymocyte differentiation, our results do not support a stochastic/selective model of lineage commitment in the thymus. Abbreviations: DP: Double positive SP: Single positive HSA: Heat-stable antigen
The Journal of Immunology, 2001
Developing T cells journey through the different thymic microenvironments while receiving signals that eventually will allow some of them to become mature naive T cells exported to the periphery. This maturation can be visualized by the phenotype of the developing cells. CCR8 is a -chemokine receptor preferentially expressed in the thymus. We have developed 8F4, an anti-mouse CCR8 mAb that is able to neutralize the ligand-induced activation of CCR8, and used it to characterize the CCR8 protein expression in the different thymocyte subsets. Taking into account the intrathymic lineage relationships, our data showed that CCR8 expression in thymus followed two transient waves along T cell maturation. The first one took place in CD4 ؊ CD8 ؊ double-negative thymocytes, which showed a low CCR8 expression, and the second wave occurred after TCR activation by the Ag-dependent positive selection in CD4 ؉ CD8 ؉ double-positive cells. From that maturation stage, CCR8 expression gradually increased as the CD4 ؉ cell differentiation proceeded, reaching a maximum at the CD4 ؉ CD8 ؊ single-positive stage. These CD4 ؉ cells expressing CCR8 were also CD69 high CD62L low thymocytes, suggesting that they still needed to undergo some differentiation step before becoming functionally competent naive T cells ready to be exported from the thymus. Interestingly, no significant amounts of CCR8 protein were detectable in CD4 ؊ CD8 ؉ thymocytes. Our data showing a clear regulation of the CCR8 protein in thymus suggest a relevant role for CCR8 in this lymphoid organ, and identify CCR8 as a possible marker of thymocyte subsets recently committed to the CD4 ؉ lineage.
Immunity, 1995
Recent studies have shown that maturation of CD4-8-double negative (DN) thymocytes to the CD4+8+ double positive (DP) stage is dependent on expression of the T cell receptor (TCR)-a polypeptide. The exact mechanism by which the TCR-0 chain regulates this maturation step remains unknown. Previous experiments had suggested that in the presence of some TCR+ thymocytes, additional DN thymocytes not expressing a TCR-0 chain may be recruited to mature to the DP stage. The recent demonstration of an immature TCR-0-CD3 complex on early thymocytes lead to the alternative hypothesis that signal transduction through an immature TCR-CD3 complex may induce maturation to the DP stage. In the latter case, maturation to the DP stage would depend on the expression of TCR-0-CD3 in the same cell. We examined these two hypotheses by studying the expression of the intra-and extracellular CD3e, CD3', and TCR-0 polypeptides in intrathymic subpopulations during embryogenesis. CD3e and CD3' were expressed intracellularly 2 and 1 d, respectively, before intracellular expression ofthe TCR-0 chain, potentially allowing immediate surface expression ofan immature TCR-(-CD3 complex as soon as functional rearrangement of a TCR-0 gene locus has been accomplished. Calcium mobilization could be induced by stimulation with anti-CD3e mAb as soon as intracellular TCR-0 was detectable, suggesting that a functional TCR-0-CD3 complex is indeed expressed on the surface of early thymocytes. From day 17 on, most cells were in the DP stage, and over 95% of the DP cells expressed on the TCR-0 chain intracellularly. At day 19 of gestation, extremely low concentrations of TCR-a chain and CD3E were detectable on the cell surface of nearly all thymocytes previously thought to be TCR-CD3 negative. These findings strongly support the hypothesis that maturation to the DP stage depends on surface expression of and subsequent signal transduction through an immature TCR-(.CD3 complex and suggest that maturation to the DP stage by recruitment, if it occurs at all, is of minor relevance.