IL-2 producing T Follicular Helper cells self restricts entry of T follicular helper cells in the germinal centers

Abstract

Abstract Upon infection or immunization, dendritic cells (DCs) present antigens (Ags) to naïve CD4 +T cells. As a result, a fraction of the responding CD4 +T cells upregulate Bcl6 and differentiate into T follicular helper (Tfh) cells, which migrate into the B cell follicles. Once in the B cell follicles, Tfh cells help promote the development and maintenance of the germinal centers (GC). Importantly, limiting the number of Tfh cells is critical for maintaining the selective pressure in the GC, thereby allowing the Darwinian selection that leads to affinity maturation. However, the mechanisms that regulate Tfh cell numbers and prevent excessive Tfh help remains unknown. Using an influenza virus infection model, we show here that Tfh cell differentiation is limited to the first 72h of the infection. After this time, whereas DCs continue to present viral antigens and efficiently prime naïve T cells, responding CD4 +T cells fail to upregulate Bcl6 and preferentially differentiate into effector Th1 cells. Mechanistically, we demonstrate that the lack of Tfh cell differentiation after day three was due to the presence of the early-primed Tfh cells. Our results indicate that early-primed Tfh cells produce large amounts of IL-2 in the proximity of the B cell follicles, thereby limiting the differentiation of new Tfh cells after day three. Collectively, our data demonstrate that early-primed Tfh cells act as a self-regulating factor that shields the B cell follicles early after infection, thereby preventing the continuous differentiation of Tfh cells regardless of the presence of viral antigens. These data demonstrate a new self-competitive mechanism that critically contributes to limiting Tfh cell expansion after infection. This work was supported by The University of Alabama at Birmingham (UAB) and the National Institutes of Health grant 1R01AI162698-01A1 to A.B.-T