SELECTION OF LYMPHOCYTES-T BEARING LIMITED T-CELL RECEPTOR-BETA CHAINS IN THE RESPONSE TO A HUMAN PATHOGEN

Delayed-type hypersensitivity (DTH) is a classic measure of T-cell responsiveness to foreign antigen. To estimate the extent of the T-cell repertoire in the DTH response to a human pathogen, we measured T-cell receptor (TCR) beta-chain variable-region (V(beta)) gene usage in reversal reactions in leprosy. Reversal reactions represent naturally occurring DTH responses in leprosy, in which augmentation of T-cell responses to Mycobacterium leprae is concomitant with clearance of bacilli from lesions. T cells using the V(beta)6-, V(beta)12-, V(beta)14-, and V(beta)19-encoded TCRs were strikingly overrepresented in the lesions of patients as compared to blood and pre-DTH lesions from the same individuals. Furthermore, these data indicate a possible association between the predominant expression of a V(beta) gene segment in lesions and the major histocompatibility complex class II haplotype of the individual. V(beta)6 was prominent in the lesions of four patients who were DR15, a marker of resistance in leprosy infection. Sequence analysis of V(beta)6 TCRs showed frequent use of V(beta)6.1 and J(beta)2.7 gene segments and a conserved amino acid motif in the V-J junction in a reversal-reaction lesion, but not in blood from the same patient. The limited TCR repertoire expressed by the infiltrating T cells suggests that a limited set of antigens is recognized in the DTH response to a human pathogen. We suggest that the mechanism by which major histocompatibility complex haplotype influences DTH in this disease involves the presentation of specific peptides, with subsequent selection of specific TCRs followed by local oligoclonal expansion.