3). Rather, we consider that lack of the DC-HIL/SD-4 pathway (inability to induce SD-4-linked inhibitory signals) leads to an enhanced T-cell response, most likely through DC-HIL co-stimulation (DC-HIL-Fc versus the native form of DC-HIL). Our recent finding that APC from DC-HIL-knockout mice become more potent T-cell

stimulators (unpublished data) is consistent with this concept. Compared with WT, SD-4-deleted T cells produced no change in T-cell response to non-specific stimuli (e.g. concanavalin A), similar to responses of find more PD-1-deleted or BTLA-deleted T cells.[20, 31, 32] In contrast, the T-cell response to anti-CD3 antibody resulted in different outcomes in the absence of APC: SD-4-deleted T cells were as responsive as the WT, whereas PD-1-deleted or BTLA-deleted T cells were hyper-reactive. This is an interesting

disparity that may be related to the fact that PD-1 and BTLA associate directly with the TCR/CD3 complex, localizing within the immunological synapse formed by the interface between T cells and APC,[33, 34] whereas SD-4 does not interact directly with the synapse.[35] Hence, absence of more proximally located co-inhibitors (PD-1 or BTLA) but not a distal one (SD-4) may directly reduce the threshold for CD3 reactivity. Note that these assays are devoid of APC. Several co-inhibitory receptors can regulate the allo-reactivity of T cells, including CTLA-4 and PD-1, which have been evaluated in GVHD. CTLA-4 acts along with the CD28–CD80/CD86 stimulation selleck inhibitor pathway to inhibit T-cell allo-reactivity.[2] Its marked influence has been suggested 4��8C by a report that polymorphisms in the CTLA-4 gene in the donors are associated with morbidity of acute GVHD.[36] In mouse models, infusion of CTLA-4-Fc, which prevents T cells from being activated by co-stimulatory signals delivered by binding of CD28 to CD80/CD86, ameliorated the lethality of GVHD.[37] However, this effect was not impressive, and this strategy was not intended to block the intrinsic regulatory

function of CTLA-4. PD-1 on T cells inhibits T-cell activation by binding to the ligands (PD-L1 and PD-L2) on APC. PD-1 expression is up-regulated in the infiltrating cells on GVHD target organs (e.g. intestine and liver) in mouse models with full MHC disparate T cells.[38] PD-1 blockade by infusion of anti-PD-1 antibody resulted in accelerated GVHD and enhanced mortality, mostly mediated by IFN-γ secretion from donor T cells.[38] Akin to our data, studies using T cells from PD-1 KO mice documented an enhanced capacity to induce GVHD. Collectively, like CTLA-4 and PD-1 receptors, SD-4 may serve as a novel target to prevent GVHD. Another difference from CTLA-4 and PD-1 is the effect on Treg-cell function. CTLA-4 on Treg cells down-regulates the expression of CD80 and CD86 on DCs, thereby making DC less activated or more tolerogenic.[39] PD-1 on naive Treg cells can convert naive T cells to inducible Treg cells in the presence of APC.