Parallel expansion of natural Foxp3+ regulatory T cells and effector CD4+ T cells recognizing the same Mycobacterium tuberculosis epitope (99.4)

Abstract

Abstract We have previously shown that regulatory T (T reg) cells restrict immunity during early Mycobacterium tuberculosis (Mtb) infection. Our experiments using T cell receptor (TCR) transgenic T reg cells suggest that T reg cells responding during Mtb infection are pathogen-specific. Nevertheless, the epitopes recognized by T reg cells have not been defined in tuberculosis or other infections. Using MHC class II tetramers containing an immunodominant Mtb epitope (specific for ESAT-64-17:I-Ab), we found that a fraction of Foxp3+ T reg cells in the pulmonary lymph node (pLN) of B6 mice during early Mtb infection were specific for ESAT-64-17, the same epitope recognized by effector CD4+ T cells. These T reg cells peaked in number at day 21 when their abundance ranged between 7-20% of all tetramer-binding cells, and disappeared by day 30-40. Interestingly, they were never observed in the lungs. ESAT-64-17-specific T reg cells expressed the transcription factor Helios, whose expression has been linked to thymically-derived natural T reg cells, suggesting that they expand from the population of pre-existing T reg cells and are not derived from conventional ESAT-64-17-specific CD4+ T cells. Moreover, ESAT-64-17-specific T reg cells use a different profile of T cell receptors than effector CD4+ T cells. We hypothesize that the expansion of pathogen-specific T reg cells may not occur in all infections, but may be driven by Mtb to assist in establishing persistent infection.