Suppression of Antigen-Specific T Cell Responses by the Kaposi's Sarcoma-Associated Herpesvirus Viral OX2 Protein and Its Cellular Orthologue, CD200

Abstract

bRegulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen-specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein. In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-␥) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200.

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…KSHV vCD200, also known as viral OX2, is a homolog of cellular CD200 that is broadly expressed and suppresses neutrophil and basophil activation (77) as well as activation of macrophages (78). vCD200 can also function as a negative regulator of antigen-specific T cell responses, including inhibition of IFN-γ production and CD107a mobilization (79).…”

Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system

“…KSHV encodes a homologue of CD200 called vCD200, which has been shown to inhibit the activation of macrophages [114], neutrophils [115] and basophils [115]. It also acts as a negative costimulatory molecule for antigen-specific T cell responses [116]. On the other hand, vCD200 has also been shown to act as positive regulator by triggering release of inflammatory cytokines (IL-1β, IL-6, MCP-1, TNF-α) [111, 117].…”

Cancers in People with HIV and AIDS

“…These events may have systemic effects long before the development of clinically apparent lymphoma and KS. For instance, KSHV encodes a homolog to CD200/ Ox2 (Foster-Cuevas et al 2004 ;Misstear et al 2012 ). Cellular CD200 is a negative regulator of infl ammation.…”