It has long been known that CD4 T cells are necessary to provide help to B cells, triggering a germinal centre (GC) reaction where affinity maturation and isotype switching occur

It has long been known that CD4 T cells are necessary to provide help to B cells, triggering a germinal centre (GC) reaction where affinity maturation and isotype switching occur. is associated with epigenetic changes.33 This suppressive effect translates in the inhibition of class\switch recombination and antibody production by B cells, and IL\21 and IL\4 production by Tfh cells. The suppressive state is reversible, as it can be abrogated in the presence of high levels of IL\21, which acts directly on both B cells (restoration of B\cell activation) and Tfr cells (inhibition of proliferation).33 In fact, this observation is usually in line with IL\21 specifically rendering Tfr cells less responsive to IL\2, in both mice and humans, and, consequently, having a negative impact on the proliferation of Tfr cells.20 VX-770 (Ivacaftor) Despite the fact that most of the suppressive capacity of Tfr cells is lost in the absence of CTLA\4, it is expected that these cells employ multiple and complementary regulatory mechanisms, as has been described for Treg cells.34, 35, 36 Several mechanisms have been proposed that involve: (i) the secretion of the regulatory cytokines IL\10 and transforming growth factor (TGF\may be an additional mechanism of Tfr suppression, as Tfh cells are suppressed by this cytokine.39 Tfr cells also express granzyme B, though in lower levels than Treg cells, and granzyme B\mediated VX-770 (Ivacaftor) cytolysis can be another regulatory mechanism employed by Tfr cells.4 Tfr cells in humans Pioneering work from Lim assays, Lim upon studies using tonsil cells spinoculated with X4 and R5 HIV have shown Tfr cell expansion (with increased CTLA\4, lymphocyte\activation gene 3 (LAG\3) and IL\10 expression) upon HIV infection in a TGF\dependent manner.62 In blood, the presence of broad neutralizing antibodies did not impact the frequency of Tfr cells, although patients with high titres of neutralizing antibodies displayed a higher expression of VX-770 (Ivacaftor) PD\1 in Tfr cells.64 Although increased PD\1 signalling has been shown to inhibit Tfr cell function in mice,17 it is still speculative to correlate the presence of broad neutralizing antibodies with putative Tfr cell exhaustion. Blood CXCR5+?Foxp3+ Tfr cells were also found increased in hepatitis B virus and hepatitis C virus chronically infected patients, showing a significant correlation with blood viral load in both infections. An increased frequency of blood CXCR5+?Foxp3+?CD45RA? Tfr cells was also found in helminthic contamination by IL\10RCD40LNEMOBTKand mutations there is a decreased frequency of Tfh cells.65 Although frequency of blood CXCR5+?Foxp3+ Tfr cells have not been studied in these pathological conditions, patients with ?2% of IgD??CD27+ B cells in the setting of common variable immunodeficiency have a reduction of blood CXCR5+?CD25hi?CD127low Tfr RB1 cell frequency, in line with a reduction of total Treg cell frequency in peripheral VX-770 (Ivacaftor) blood.66 This study suggests a relationship between this B\cell subset and blood Tfr cells, but the clinical heterogeneity and largely unknown molecular mechanisms driving common variable immunodeficiency preclude a definite conclusion about blood Tfr cell ontogeny. Recently, the SOCE (store\operated calcium entry) pathway in T cells has been implicated in Tfr cell differentiation in humans, as patients with severe combined immunodeficiency\like disease due to inherited loss\of\function mutations in and genes that abolish SOCE have a significant reduction in blood CD45RO+?Helios+?Foxp3+ Tfr\like cells.67 In another recent study, IL\21R\deficienct patients have been shown to have a significant increase in frequency of blood Foxp3+?CXCR5+?PD\1+ Tfr cells. In contrast, a marked decrease in circulating CXCR5+?PD\1+ Tfh cells was observed in IL\21R\deficiency patients.20 Taken together, these recent studies suggest that human Tfh and Tfr cells have different, sometimes reciprocal, requirements for their differentiation. Therefore, the impact of the IL\21CIL\2 axis in Tfh and Tfr balance deserves further investigation, as its modulation may influence the outcome of GC responses. Conclusions The GC reaction is a key event in humoral responses. The B\cellCTfh cell interactions are important for the production of high\affinity protective antibodies, following B\cell.