A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma

Abstract

Programmed death one homolog (PD-1H) is a cell surface molecule of the B7/CD28 immune modulatory gene family. Although PD-1H has been shown to function as a coinhibitory receptor on T cells to limit naive T-cell activation and proliferation, its role in the regulation of the T-cell response to allergens is unknown. We report here that genetic ablation or blockade of PD-1H drastically promotes pulmonary inflammation with massive accumulation of eosinophils in a mouse model of experimental asthma, indicating a suppressive function of PD-1H in allergic inflammation. The loss of PD-1H led to elevated production of both innate cytokines (IL-6, MCP-1 and TNFα) and Th2 cytokines (IL-5 and IL-13) in the lung, indicating a critical role of PD-1H in suppressing the production of airway inflammatory cytokines. In addition, the loss of PD-1H also impaired the expansion of systemic and pulmonary regulatory T cells during asthma induction. These findings support a critical role of intrinsic PD-1H in the regulation of inflammatory responses to allergens. Finally, we showed that treatment with a PD-1H agonistic monoclonal antibody reduced the severity of asthma, which was accompanied by suppressed lung inflammation. Our findings support PD-1H as a potential target and suggest a possible strategy for the treatment of allergic asthma in humans.

VISTA: Coming of age as a multi-lineage immune checkpoint

“…Similar results were recently reported in the Fas lpr lupus model where VISTA‐deficiency enhanced disease while VISTA agonists suppressed both cutaneous and systemic lupus . In addition, VISTA‐deficiency was shown to exacerbate allergic inflammation and experimental asthma, suggesting a role in the regulation of type II immunity . VISTA −/− mice were also more susceptible to concanavalin A (ConA)‐induced lethality .…”

“…VISTA is also composed of a single IgV domain and therefore, based on structural insights, we predict that VISTA probably functions primarily as a receptor. This has been corroborated by a number of studies that elucidated the receptor role for VISTA using multiple systems . The second evidence for VISTA function is the ability to impart opposing outcomes of immune responses using agonist and antagonist antibodies.…”

The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation

“…Studies by Flies et al have shown that in a murine model of experimental asthma, allergen challenge induced higher levels of Th2 cytokine production and more severe pulmonary inflammation in Vsir −/− mice. 55 THE LIGAND-OR-RECEPTOR PARADIGM BY WHICH VISTA REGULATES T CELL ACTIVATION Due to the lack of knowledge on the cognate receptor for VISTA or associated signaling adaptors, the molecular mechanisms of how VISTA regulates effector T cell activation are not well understood. Despite this limitation, recent studies have demonstrated both cell-extrinsic and intrinsic mechanisms by which VISTA regulates T cell responses.…”

VISTA Is Crucial for Corneal Allograft Survival and Maintenance of Immune Privilege

“…14 Various studies have investigated that that VISTA regulates Tcell responses in various murine models of carcinoma, autoimmune and allergic disease. 14,[18][19][20][21][22][23] Anti-VISTA treatment exacerbates the development of the T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis in mice. 14 VISTA À/À T cells induce exacerbated graft-versus-host disease compared to wild-type T cells.…”

“…20 VISTA deficiency or blockade of VISTA also accelerated asthmatic responses. 21,23 Antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L have become new therapies for cancer. [24][25][26][27][28][29] VISTA expression also plays a critical role in shaping anti-tumor immunity.…”