Germinal centers (GCs) are key structures where B cells are selected to produce high affinity immunoglobulins of the adequate class. This selection is dependent of B cell interactions with specialized follicular helper T (Tfh) cells that provide help for class switch recombination, somatic hypermutation, and selection signals to GC B cells. It was recently described that the GC reaction is controlled by specialized Foxp3+ follicular regulatory T (Tfr) cells. These cells regulate the size and magnitude of the GC reaction, and have been also implicated in the prevention of autoimmunity. This thesis aimed to answer two questions regarding Tfr cells biology. First, it was investigated whether Tfr cells derive from thymic-derived regulatory T (tTreg) cells. The second objective was to establish whether Tfr cells are specific for the non-self antigen driving the GC response, as Tfh cells, or if Tfr cells have a repertoire closer to Treg cells with specificity towards self-antigens. It was found that Tfr cells originate exclusively from tTreg cells. Also, Tfr cells were not specific for the immunizing antigen. Indeed, as antigen-specific TCR-transgenic Tfr cells were not specifically recruited into the GC, nor could antigen-specific Tfr cells be detected using class-II MHC tetramers. Moreover, Tfr cells did not specifically proliferate in vitro when stimulated with the immunizing antigen. Lastly, repertoire analysis of Tfr, Treg and Tfh cells demonstrated that Tfh cells and Tfr cells have different repertoires with the latter retaining a repertoire closer to Treg cells. Taken together, the presented results show a clear difference in the specificity and TCR usage by Tfh and Tfr populations from the same GCs. This distinct specificity is in line with different putative functions of the two populations: while Tfh cells promote antigen-specific B cell responses, Tfr cells prevent autoimmunity.

Tese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2017