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Mycobacterium bovis Strain Bacillus Calmette-Guérin-Induced Liver Granulomas Contain a Diverse TCR Repertoire, but a Monoclonal T Cell Population Is Sufficient for Protective Granuloma Formation¹

Laura H. Hogan^2,*, Khen Macvilay^*, Brittany Barger^*, Dominic Co^*, Irena Malkovska^*, Glenn Fennelly and Matyas Sandor^*

^* Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, WI 53706; and Department of Pediatrics, Jacobi Medical Center and Albert Einstein College of Medicine, Brooklyn, NY 10461

Granuloma formation is a form of delayed-type hypersensitivity requiring CD4⁺ T cells. Granulomas control the growth and dissemination of pathogens, preventing host inflammation from harming surrounding tissues. Using a murine model of Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) infection we studied the extent of T cell heterogeneity present in liver granulomas. We demonstrate that the TCR repertoire of granuloma-infiltrating T cells is very diverse even at the single-granuloma level, suggesting that before granuloma closure, a large number of different T cells are recruited to the lesion. At the same time, the TCR repertoire is selected, because AND TCR transgenic T cells (V11/V3 anti-pigeon cytochrome c) are preferentially excluded from granulomas of BCG-infected AND mice, and cells expressing secondary endemic V-chains are enriched among AND cells homing to granulomas. Next, we addressed whether TCR heterogeneity is required for effective granuloma formation. We infected 5CC7/recombinase-activating gene 2^-/- mice with recombinant BCG that express pigeon cytochrome c peptide in a mycobacterial 19-kDa bacterial surface lipoprotein. A CD4⁺ T cell with a single specificity in the absence of CD8⁺ T cells is sufficient to form granulomas and adequately control bacteria. Our study shows that expanded monoclonal T cell populations can be protective in mycobacterial infection.

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