Differential role for CD277 as a co‐regulator of the immune signal in T and NK cells

Abstract

The human butyrophilin (BTN) 3 or CD277 molecules belong to the B7 family members and are expressed in various immune cells such as T and NK cells. Here, we show that CD277 triggering considerably enhances TCR-induced cytokine production and cell proliferation, even when another co-stimulatory molecule, CD28, is engaged. These CD277-induced additive functional effects are in accordance with the detection of early T-cell activation events such as TCR-induced cell signaling being increased upon CD277 engagement. However, we found that CD277 triggering is not involved in CD16-or NKp46-induced NK cell activation. BTN3/CD277 comprises three structurally related members, BTN3A1, BTN3A2 and BTN3A3. CD277 antibodies recognize all isoforms and we describe a differential expression of BTN3 isoforms between T and NK cells that could explain differential CD277 functions between T and NK cells. Our results show that, while T cells express all BTN3/CD277 transcripts, NK cells express mostly BTN3A2, which lacks the B30.2 intracellular domain. Furthermore, NKp30-induced cytokine production is decreased by the specific engagement of BTN3A2, but not by BTN3A1 triggering. Thus, we provide new insights into the CD277 co-stimulatory pathway that may differentially participate in the regulation of various cell-mediated immune responses.

Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

“…Accordingly, soluble 20.1 mAb induced: ex vivo production of IFN-␥ and TNF-␣ by ␥␦ T cells ( Figure 1B), rapid CD69 up-regulation and IFN-␥ production by most V␦2 ϩ -␥␦ PBL ex vivo ( Figure 1C; supplemental Figure 1B), and degranulation and cytokine responses of V␥9V␦2 T-cell clones specifically ( Figure 1D; data not shown). In agreement with recent studies, 23,25 soluble 20.1 mAb had no stimulatory effect on ␣␤ T cells. Moreover, it had no effect on V␦2 Ϫ -␥␦ PBL ( Figure 1C) or T-cell clones ( Figure 1D).…”

“…23,25 They can also modulate T-cell costimulatory or coinhibitory signals through interactions with target cell-expressed CD277. 24,34 Thus, although anti-CD277 mAb readily induced V␥9V␦2 T-cell activation in the absence of third-party cells, this could be the result of either a "direct" or "cis" effect of the Ab (CD277-induced signaling in responder V␥9V␦2 T cells) or an "indirect" or "trans" effect (enhanced reactivity of V␥9V␦2 T cells toward anti-CD277-coated T cells).…”

“…Costimulatory activity of mAb 20.1 on TCR-stimulated ␣␤ T cells has been reported with plate-bound mAb only and is the consequence of direct engagement of CD277 expressed by responder T cells. 25 In marked contrast, soluble, but not immobilized, mAb 20.1 induced full activation of V␥9V␦2 T cells in the absence of any other stimuli (eg, anti-CD3 mAb) and acted primarily, if not exclusively, in an indirect manner (ie, through sensitization of CD277 ϩ target cells to V␥9V␦2 T-cell recognition. Yamashiro et al also described inhibition of anti-CD3-stimulated ␣␤ T cells by a high-affinity anti-CD277 mAb able to induce CD277 phosphorylation in T cells.…”

“…17,20,21 This can result from either direct engagement of BTN receptors expressed on responding T cells by target cell ligands, or interactions involving target cell BTN molecules and responding T cell-derived ligands. [22][23][24][25] In this study, we provide evidence that ubiquitous human CD277/BTN3A plays a key role in PAg-induced activation of V␥9V␦2 T cells in both tumor and infectious contexts and that CD277-dependent activation is conferred by V␥9V␦2 TCR. Our results suggest that intracellular PAg accumulation is associated with membrane reorganization of CD277 molecules, which in turn leads to V␥9V␦2 T-cell activation, and bring new insights into the mechanisms linking metabolic and infectious distress and human ␥␦ T-cell activation.…”

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

“…As BTN3A2 lacks the intracellular B30.2 domain, it has been hypothesized to be a decoy receptor via the binding of a putative ligand. 31 Its predominant expression by AML blasts could constitute an immune escape mechanism to Vg9Vd2 T cells recognition. However, we assume that anti-BTN3A 20.1 mAb could by-pass N-BP resistance via the triggering of BTN3A2, through mechanisms involving decreased mobility 20 and a multimerization of BTN3A molecules.…”