Influence of human leukocyte antigen genes on TCR V gene segment frequencies

Abstract

Human leukocyte antigen (HLA)-dependent selection mechanisms exerted during thymic maturation are supposed to be main contributing factors to the genetic predetermination of the TCR repertoire and may have a detectable effect on adult peripheral blood lymphocyte V segment frequencies. Here, we analyzed whether polymorphic or non-polymorphic HLA determinants are associated with selected expression of some V gene segment specificities. We first examined the reactivity of 17 V segment specific mAb on purified CD4+ and CD8+ cell fractions in 10 unrelated people. We found a significant overexpression of only three V segment products (V beta 2, V beta 5.1 and V beta 6.7) in CD4+ and none in CD8+ cell fractions in most individuals. Skewing of certain V beta segments by non-polymorphic HLA determinants (i.e. class II for CD4+ and class I for CD8+ cells) is therefore more limited (3/17) than previously thought. Considering the effects of polymorphic HLA determinants, we compared TCR V segment frequencies in HLA-identical siblings to sibling pairs who differ at one or both HLA haplotypes, using 13 V beta specific mAb. In pairwise comparisons, we found that the HLA complex had no detectable effect on TCR repertoire in five large families with multiple siblings. Together, these observations suggest that HLA-predicted selection mechanisms exerted during thymic maturation might not have a predominant influence shaping the TCR repertoire of normal adults.

Contribution of TCR-β Locus and HLA to the Shape of the Mature Human Vβ Repertoire

“…However, HLA identical siblings share not only HLA identity but also genomic identity and thus such an analysis is confounded by HLA-independent factors. Alternatively, the analysis of a limited set of V␤ proteins (4 -9) may have confounded these studies as well because others analyzing 13 V␤ proteins in individuals from five multisibling families could not confirm previous findings (39). In quantifying the contribution of different factors to the hierarchy of V␤ expression in humans, we observed that there is a significant correlation even when TCR-␤ allelic effects and HLA have been excluded, suggesting that factors generic to the TCR locus play a major role in determining V␤ expression patterns.…”

Evidence for Restricted Vβ Usage in the Leukemic Phase of Cutaneous T Cell Lymphoma

“…The first possibility is that the frequent Vb5.1 usage simply reflects the fact that Vb5.1 is expressed to a greater degree by CD4 þ than CD8 þ T cells (Grunewald et al, 1991;Genevé e et al, 1994;Reed et al, 1994;Shigematsu et al, 1996; van den Beemd et al, 2000) This, however, cannot be the entire explanation because Vb2 segments are expressed to an even greater degree by CD4 þ cells and these segments are infrequently identified in leukemic CTCL. Another possibility is that Vb5.1-bearing T cells may be inherently more prone to undergo malignant transformation relative to other Vb families.…”

“…It is thought that differences in reactivity between MHC molecules and Vb segments in the thymus influences the Vb repertoire of CD4 þ and CD8 þ cells, and that this accounts for the increased expression of Vb2, Vb5.1, Vb6.7, Vb8, and Vb12 on CD4 þ cells compared with CD8 þ cells (Grunewald et al, 1991;Genevé e et al, 1994;Reed et al, 1994;Shigematsu et al, 1996;van den Beemd et al, 2000).…”

HLA-dependent peripheral T cell receptor (TCR) repertoire formation and its modification by rheumatoid arthritis (RA)

“…This suggested that the TCRB gene repertoire is controlled primarily by genetic factors. Although still controversial [3][4][5], HLA appears to be a major genetic factor moulding the TCRBV repertoire.…”