The checkpoint inhibitors, anti-CTLA-4 and PD-1, are being used to maximize helper T-cell activity, first in T-cell zones to promote early B-cell recruitment and expansion and later in GCs to increase TFH activity

The checkpoint inhibitors, anti-CTLA-4 and PD-1, are being used to maximize helper T-cell activity, first in T-cell zones to promote early B-cell recruitment and expansion and later in GCs to increase TFH activity. defined by their constitutive expression of the IL-2 receptor chain (CD25), CTLA-4, and the tumor necrosis factor (TNF)-receptor family members GITR (glucocorticoid-induced TNF receptorCrelated protein) and OX40.62 As these molecules are expressed by many lymphocytes, Foxp3 remains the definitive signature of TReg cells.44 Despite extensive study, the mechanism by which TReg cells suppress immune responses in vivo is not well understood. TReg cells may inhibit responses indirectly by modulating antigen-presenting cell function, 63 directly by secreting anti-inflammatory cytokines,64,65 and/or by inducing production of indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan, and consequently promotes T-cell quiescence and apoptosis.66,67 Just which suppressive mechanisms are employed by TReg cells is unclear, but in most, if not all cases, such mechanisms are likely redundant and may vary by tissue site or the degree of inflammation.62 A recently described class of TReg cells is the follicular TReg (TFReg) cell.68C70 As their name implies, TFReg cells enter GCs and interact with resident follicular T-helper cells (TFH) to regulate B-cell expansion, mutation, and V(D)J hypermutation. As the primary site of B-cell hypermutation and class-switch recombination, the GC response is well regulated to minimize generation of autoantibody, systemic autoimmune disease, pathological inflammation, and B-cell malignancy. Among these regulatory mechanisms, TFReg cells specifically and potently suppress both TFH and B cells in GCs.68C71 TFReg cells are likely essential for the physiological homeostasis of GC reactions and may play a crucial role in determining GC persistence and, possibly, clonal selection. In the context of improved HIV-1 vaccines, TFReg activity may be a controlling factor in the prevention of vaccine-induced bNAb development, either by limiting GC persistence to effectively reduce the acquisition of V(D)J mutations or by aiding in the removal of autoreactive mutant B cells. Either activity would have significant consequences. For example, in bNAbs, V(D)J hypermutation is frequent not only in the antigen-contacting CDRs, but also in the antibody framework regions responsible for maintaining antibody structure; remarkably, these framework mutations may be necessary for bNAb breadth and potency.72 Somatic mutation can also generate de novo hotspots for activation-induced cytidine deaminase (AID) activity in V(D)J rearrangements, creating template sites prone to Irinotecan HCl Trihydrate (Campto) insertion/deletion mutations73; in some cases, the occurrence of an insertional event is critical to acquisition of bNAb activity.73 Thus, merely by limiting GC persistence, TFReg activity might block the possibility vaccine-induced bNAb production. 4 | VACCINE TRANSIENT IMMUNE MODULATION FOR BNAB INDUCTION The very properties that appear to be required for bNAb activity, extended HCDR3 regions, high frequencies of V(D)J mutation, poly- or autoreactivity are also properties that disfavor B-cell development and survival. Given that immunological tolerance shapes the primary BCR repertoire, only B cells that have been vetted Irinotecan HCl Trihydrate (Campto) by tolerance are available to respond Rabbit polyclonal to ZNF184 to vaccines; for vaccine antigens that mimic self-antigens, the pool of mature B cells that can respond will be reduced. These predicted effects have been amply demonstrated in bNAb KI mouse lines (Table 1) and are consistent with atypical pathways of bNAb evolution normally proscribed by the effects of peripheral tolerance.3 The unusually low efficiency with which immunization elicits Irinotecan HCl Trihydrate (Campto) bNAbs implies that bNAb B cells are the products of disfavored clonal evolution. In consequence, we propose that checkpoint inhibitors and.