Influence of HLA-DR on the phenotype of CD4(+) T lymphocytes specific for an epitope of the 16-kDa alpha-crystallin antigen of Mycobacterium tuberculosis

T helper phenotype may be influenced by cytokine milieu, the differential e xpression of costimulatory molecules, antigen dose, and by differences in a ffinity at the TCR-peptide-MHC interface. We investigated the latter hypoth esis by examining the response of six HLA-DR-restricted CD4(+) T cell lines specific for the immunodominant and permissively recognized p91-110 epitop e of the 18-kDa alpha-crystallin protein of Mycobacterium tuberculosis. Eac h line was generated from a sensitized HLA-DR-heterozygous donor and all pr oliferated when peptide was presented by autologous irradiated peripheral b lood mononuclear cells. However, when HLA-DR-matched homozygous Epstein-Bar r-Virus-transformed B cell lines (L-BCL) were used as peptide-presenting ce lls there was heterogeneity in the response. The most pronounced proliferat ive response, and the highest IFN-gamma secretion and cytolytic activity wa s stimulated by L-BCL expressing molecules (DRB1*0101, *1501 and *0401) wit h high affinity (IC50 < 10 mu M) for the 16p91-110 peptide. By comparison, IL-4 secretion or a lower proliferative response could occur when peptide w as presented by alleles of high, or of intermediate (10 mu M < IC50 < 100 m u M) affinity. These data support the hypothesis that the host MHC can infl uence CD4(+) phenotype and have implications for subunit vaccination agains t tuberculosis.