Variability in T cell receptor V beta gene usage in human peripheral blood lymphocytes. Studies of identical twins, siblings, and insulin-dependent diabetes mellitus patients.
Recent studies focused on the diversity and molecular organization of the human TCR-beta complex have begun to establish the genetic basis for the potential repertoire of V beta specificities in T cells. The scope and variability of the actual repertoire derived from this potential repertoire, however, remains to be clarified. In this study, V beta usage by human peripheral T cells derived from serial samples of the same individual, identical twins, and the members of three nuclear families that include four members with insulin-dependent diabetes mellitus (IDDM) was assessed by both quantitative polymerase chain reaction and Northern blotting with V beta subfamily-specific probes. Samples taken from the same individual over a period of 21 months and analyzed in separate experiments indicated stability in the peripheral repertoire, whereas the similarity in peripheral V beta usage in a pair of identical twins suggested a strong role for genetics in shaping the peripheral T cell repertoire. In contrast, V beta usage in siblings and in unrelated individuals was observed to differ substantially. In particular, peripheral expression of V beta 3 and V beta 20 differed by more than sixfold among members of two different families. Segregation analysis of TCR and HLA haplotypes in these families suggested that variation in V beta 20 expression was TCR haplotype specific. Subsequent nucleotide sequence analysis of the V beta 20 gene segment in multiple members of these families revealed the presence of a null allele for V beta 20 expression. No consistent significant differences in V beta usage were observed in IDDM patients relative to their siblings or between identical twins discordant for IDDM. These results suggest that the repertoire of peripheral T cell specificities present in different individuals in human populations varies dramatically because of the effects of multiple factors, including TCR germ-line polymorphism.
Malhotra
U
U
Virginia Mason Research Center, Seattle, WA 98101.
Spielman
R
R
Concannon
P
P
D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D014430:Twins, Monozygotic
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta