Requirements for CD4+ T cell levels in acute Mycobacterium bovis strain bacille Calmette Guérin (BCG)-induced granulomas differ for optimal mycobacterial control versus granuloma formation

Bacille Calmette Guerin (BCG)-induced granulomas contain T cells that express a broad TCR repertoire even at the level of the individual lesion. We have developed a BCG infection model in mice having only one T cell specific for a recombinant BCG epitope expressed in a lipoprotein fusion protein. Here we report that the single T cell model induces well-formed granulomas, but has weaker protection than that conferred by wild-type granulomas. This finding correlates with lower CD4+ T cell recruitment into acute granulomas (3 weeks post infection). Chronic granulomas (6 weeks post infection) contain similar proportions of CD4+ T cells in both models, but in the single T cell model the proportion of leukocyte function-associated antigen-1 low, non-IFNγ-producing CD4+ T cells is lower. In fact, even though it is likely that there are very few, if any, IFNγ+ CD4+ T cells present in the single T cell model, granuloma integrity is not influenced, indicating that high levels of IFNγ are not required for granuloma maintenance. These data underline the importance of early CD4+ T cell recruitment into the granuloma to anti-mycobacterial protection and show that CD4+ T cell levels required for granuloma formation and optimal protection are different. These data also show that T cell repertoire complexity contributes to protection against mycobacteria.