TCR Repertoire, Clonal Dominance, and Pulmonary Trafficking of Mycobacterium-Specific CD4+ and CD8+ T Effector Cells in Immunity Against Tuberculosis

Clonal responses of Mycobacterium tuberculosis-specific CD4(+) or CD8(+) T effector cells producing antituberculosis cytokine IFN-gamma in the context of immune protection against tuberculosis remain poorly characterized in humans. Utilizing decade-long TCR expertise, we previously developed a useful method to isolate clonotypic TCR sequences from Ag-specific IFN-gamma-producing T cells and to specifically measure clonotypic TCR frequencies in the T cell pool. In this study, we investigated TCR V beta repertoires/CDR3 usage, clonal expansion or dominance, and pulmonary trafficking or accumulation for purified protein deritative (PPD)-specific T effector cells producing IFN-gamma during bacillus Calmette-Guerin (BCG) vaccination and subsequent M. tuberculosis challenge of macaques. We found that while PPD-specific CD4(+) and CD8(+) T effector clones employed diverse TCR Vb repertoires, 30-33% of IFN-gamma(+)CD4(+) T cell clones from three M. tuberculosis-infected macaques expressed TCR bearing a conserved residue leucine in CDR3. Many Ag-specific IFN-gamma(+)CD4(+) and few CD8(+) T effector cells emerged as dominant clones during mycobacterial infections and underwent major recall expansion after pulmonary M. tuberculosis infection of BCG-vaccinated macaques. PPD-specific T cell clones readily trafficked to the airway or lung after BCG vaccination or M. tuberculosis infection, and some of them continuously accumulated in lungs during M. tuberculosis infection even after they became undetectable in the circulation. Importantly, remarkable recall expansion and pulmonary accumulation of Teffector cells coincided with BCG-induced protection against tuberculosis. Thus, rapid clonal expansion and pulmonary accumulation of Ag-specific T effector cells appear to be one of the immune mechanisms underlying immunity against tuberculosis. The Journal of Immunology, 2010, 185: 3940-3947.