Expression of Leukocyte Immunoglobulin-Like Receptors and Natural Killer Receptors on Virus-Specific CD8⁺T Cells during the Evolution of Epstein-Barr Virus-Specific Immune Responsesin Vivo

Abstract

Antigen-primed cytotoxic T lymphocytes (CTL) may express leukocyte immunoglobulin-like receptors (LILRs) and natural killer receptors (NKRs). Published work suggests that expression of some of these receptors confers survival advantage, leading to the idea that cells expressing such receptors may accumulate as an antigen-specific response evolves. Here we tested this hypothesis by analyzing expression of CD85j (also known as LILRB1 or ILT2), KIRs, CD94, and CD161 by Epstein- Barr virus (EBV)-specific CTL during the primary and persistent phases of EBV infection in humans. During primary infection, few EBV-specific CTL expressed these receptors and this proportion was equally low in early persistent infection. Thus, expression of these molecules does not influence capacity to survive downregulation of the primary response. However, in donors persistently infected with EBV for many years, a significantly higher proportion of EBV-specific CTL expressed CD85j and NKRs, suggesting that cells expressing these receptors can accumulate with time. Using FACS analysis, we confirmed, at a single cell level, that expression of CD85j, defined by staining with the antibody VMP55, was associated with reduced capacity of EBV-specific CD8+ T cells to respond to antigen. Thus, in the later stages of persistent infection, protective immunity to EBV may be reduced due to the preferential accumulation of hyporesponsive EBV-specific CD8+ T cells.

NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies

“…Although the mechanism(s) underlying the late expansion of the NKG2C ϩ NK-cell subset in response to HCMV infection 15 remain unknown, the phenomenon is reminiscent of the expansion of circulating virus-specific specific cytotoxic T lymphocyte displaying a terminally differentiated phenotype, often associated with NKR expression, which exhibit reduced effector functions against virus-infected cells. 50 In conclusion, our results support that human NK cells are capable of effectively counteracting viral immune evasion strategies and responding to infected moDCs that have impaired their antigen-presenting functions, thus indirectly favoring the development of adaptive immune responses to viral antigens crosspresented by healthy DCs.…”

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

“…Besides dengue, human cytomegalovirus (HCMV) also binds LILRB1 through the glycoprotein UL-18 to trigger an inhibitory signaling pathway that limits antiviral effector functions (21,22). Furthermore, increased LILRB1 expression in CD8 + effector T-cells is associated with reduced cytokine secretion and cytotoxicity in persistent HCMV and Epstein-Barr virus infections (22,23). It would be interesting to test if LILRB1-mediated suppression of immune signaling is also exploited by other viruses.…”

Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

“…The LILRB1 inhibitory receptor is expressed at late differentiation stages by cytotoxic T lymphocytes specific for different microbial pathogens [49][50][51][52]. Similarly to T lymphocytes, activated NK cells undergo clonal expansions, experiencing differentiation events that modify their phenotype and survival [42,53].…”