TH1 or TFH-type 1 cells express high levels of type 1 cytokines such as interferon-gamma but no or low levels of IL-21. donors (mostly white), namely Rh-C, -E and K, has been a strategy used to reduce alloimmunization in patients with SCD; however, patients transfused with C,E,K-matched donor RBC (from mostly black donors), can still develop pathogenic Rh antibodies due to the Diosmetin-7-O-beta-D-glucopyranoside genetic diversity of the locus in individuals of African ancestry.2,3 This highlights the need for better characterization of alloimmunization triggers and risk factors/biomarkers in this highly vulnerable population. The etiology of alloimmunization in patients with SCD remains unclear. Our group has recently studied antigen-specific CD4+ helper T-cell responses in peripheral blood of Diosmetin-7-O-beta-D-glucopyranoside transfused patients with SCD.4 We found that in alloantibody responder patients, antigen-specific CD4+ T-cell responses were predominantly TH17, and that interleukin (IL)-21, the prototypic follicular helper T-cell (TFH)-associated cytokine driving B-cell help, was only expressed by antigen-specific TFH derived from responders.4 These data are consistent with the role of heightened CD4+ T-cell effector functions driving alloantibody production in alloimmunized SCD patients. TFH cells have emerged as the main effector CD4+ T cells specialized in providing help to support responses of antigen-engaged B cells to generate the initial wave of antibody response as well as in supporting B-cell differentiation into high affinity antibody-producing B cells and long-lasting IgG antibodies.5 TFH cells are universally characterized by: Rabbit Polyclonal to ADCK2 (i) the expression of the chemokine (C-X-C motif) receptor 5 (CXCR5) on Diosmetin-7-O-beta-D-glucopyranoside memory (CD45RA?) cells which directs them to the B-cell follicles in response to the specific ligand CXCL13;6C8 (ii) expression of IL-21, a potent cytokine promoting growth, differentiation, and class switching of B cells although they also secrete other B-cell help cytokines including IL-4;9,10 and (iii) co-stimulatory molecules specialized in providing B-cell help including inducible T-cell co-stimulatory (ICOS) and CD40L.5,11 Given the key role of TFH cells in providing help to B cells to support their activation, expansion and differentiation, these cells have attracted particular attention as potential targets for developing therapeutic strategies not only to enhance vaccination responses but also to prevent antibody-mediated autoimmunity.5 Our studies of antigen-specific TFH responses in alloimmunized SCD patients support the notion that TFH cells are also likely to be critical in alloimmunization biology.4 More recently, TFH-related cells with ability to promote antibody responses were identified in the peripheral circulation of humans and mice,12C19 opening up the possibility of studying TFH cell responses in blood samples. Open in a separate window Figure 1. Hypothesized model of TIGIT+ circulating follicular helper T-cell differentiation following chronic stimulation. TH1 or TFH-type 1 cells express high levels of type 1 cytokines such as interferon-gamma but no or low levels of IL-21. Upon chronic stimulation such as following regular transfusions, these T cells become exhausted, losing the ability to produce interferon-gamma. At the same time, immune checkpoint molecules, including TIGIT and PD-1, are up-regulated and the cells express the prototypic B-cell help cytokine IL-21, which subsequently drives antibody production by B cells. In the report from Yazdanbakhshs group published in this issue of the journal,20 Godefroy examine the role of two immune checkpoints21 expressed by CD4+/CD45RA?/CXCR5+ circulating follicular helper T (cTFH) cells: the programmed cell death-1 (PD-1) and the T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT) surface molecules. The function of PD-1 on TFH cells remains controversial and has been described as both promoting15,16 and reducing17,22,23 humoral responses in different models. The recent discovery of regulatory follicular T cells (TFR) expressing high levels of PD-117 may help to reconcile these divergent findings. Although TIGIT expression on T cells has been studied previously,24C29 the function of TIGIT on TFH cells is being addressed for the first time in the study by Godefroy also demonstrated that whereas PD-1 did not seem to play a major role in this system, TIGIT was directly implicated in the function of these cells.20 Indeed, blocking TIGIT not only decreased the expression levels of ICOS, CD40L and IL-21, but also prevented B cells from producing IgG.10 Other authors proposed a direct role for PD-1 in TFH function.15C17,22,23 In the study by Godefroy propose an interesting model in which repeated exposure to allogeneic red blood cells in patients with.