Thymic skewing of the CD4/CD8 ratio maps with the T-cell receptor α-chain locus

Abstract

The thymic preference for CD4+ T cells over CD8+ T cells is often attributed to a default pathway favouring CD4+ T cells or to homeostatic mechanisms. It is also clear, however, that T-cell receptor (TCR) preferences for major histocompatibility complex (MHC) class I versus class II binding will strongly influence an individual clone's skewing to the CD4 or CD8 subset. The variable region of each TCR alpha chain (V alpha) studied to date is found to be overrepresented in either CD4+ or CD8+ cells, suggesting that each V alpha element can interact more favourably with either MHC class I or class II molecules. Indeed, TCRs appear to have an intrinsic ability to interact with MHC molecules, and single amino acid residues present in germline-encoded complementarity determining region 1 (CDR1) and CDR2 of the V alpha element can be responsible for determining MHC specificity. Interestingly, the degree of CD4/CD8 skewing is variable among different mouse strains and in human populations. Here, we have shown that polymorphism in CD4/CD8 skewing between B6 and BALB/c mice is determined by the stem cell genotype and not by environmental effects, and that it maps in or near the TCR alpha-chain complex, Tcra. This was confirmed by comparing Tcra(b) with Tcra(a) or Tcra(c) haplotypes in congenic mice. We propose that the array of V alpha genes in various Tcra haplotypes exerts influence over the proportion of CD4 and CD8 subsets generated and may account in part for the observed thymic skewing. Thus, while it has been suggested that the TCR genes have been selected by evolution for MHC binding, our results further indicate selection for class II MHC preference.

Thymocyte-Intrinsic Genetic Factors Influence CD8 T Cell Lineage Commitment and Affect Selection of a Tumor-Reactive TCR

“…In some mouse combinations, this trait was mapped to the TCR␣ chain locus, suggesting that it was the consequence of a preference for MHC class II selection by a given array of V␣ genes characterizing a TCR␣ haplotype (33). However, the higher CD4/CD8 T cell ratio in DBA/2 as compared with C57BL/6 mice was not linked to either TCR␣ or TCR␤ loci, and was independent of MHC haplotype (20).…”

Linkage analysis of variations in CD4:CD8 T cell subsets between C57BL/6 and DBA/2

“…Sim et al 14 showed that the ratios of these cells are affected in the thymus by genes mapping to the TCR␣ locus. Several recent publications have shown that the size of the CD8 + population in the thymus can be increased by increased expression of proteins thought to improve lymphocyte survival such as notch 23 and bcl-2.…”

“…Figures 3 and 4 present the results of these scans for the relevant chromosomes together with results for chromosomes 14 (TCR␣) and 6 (TCR␤), which have been implicated in control of CD4:CD8 ratio by previous scans. 14 Two genomic segments significantly associated with CD4:CD8 ratios in peripheral organs were identified, based on criteria established by Lander and Kruglyak. 22 The first, designated Trmq1 (for T cell ratio modifier QTL 1), mapped to the telomeric end of c6 (peak marker D6Mit15 at 74 cM) and was found in the F2 cross ( Figure 3b).…”

“…[9][10][11] Although environmental and other factors may affect the numbers of CD4 to CD8 T cells in an individual, it is clear that the ratio is also under genetic control. [12][13][14] Since the maturation of CD4 and CD8 T cells is controlled by interactions of their ␣␤ T cell receptors with class II and class I major histocompatibility complex proteins (MHC) and peptides in the thymus, one would predict that CD4 to CD8 ratios would be affected by TCR and MHC genes. Indeed there is evidence that in certain mouse strain combinations, this is the case.…”

“…Indeed there is evidence that in certain mouse strain combinations, this is the case. 14,15 Other proteins expressed in the thymus, such as Notch, may also affect the balance between CD4 and CD8 T cells. 16 The correlation between the ratio of CD4 to CD8 T cells in the thymus and periphery is not always good, however.…”