Abstract
SummaryCD8+ T cell recognition of virus-infected cells is characteristically restricted by major histocompatibility complex (MHC) class I, although rare examples of MHC class II restriction have been reported in Cd4-deficient mice and a macaque SIV vaccine trial using a recombinant cytomegalovirus vector. Here, we demonstrate the presence of human leukocyte antigen (HLA) class II-restricted CD8+ T cell responses with antiviral properties in a small subset of HIV-infected individuals. In these individuals, T cell receptor β (TCRβ) analysis revealed that class II-restricted CD8+ T cells underwent clonal expansion and mediated killing of HIV-infected cells. In one case, these cells comprised 12% of circulating CD8+ T cells, and TCRα analysis revealed two distinct co-expressed TCRα chains, with only one contributing to binding of the class II HLA-peptide complex. These data indicate that class II-restricted CD8+ T cell responses can exist in a chronic human viral infection, and may contribute to immune control.
Highlights
Antigen-specific CD8+ T cells are a major defense against invading viruses, killing infected cells harboring non-self proteins
Double-positive T cells undergo a maturation process where they are selected as either CD8+ T cells or CD4+ T cells depending on T cell receptor (TCR) binding to peptide complexed with major histocompatibility complex (MHC) class I or class II, respectively
CD8+ T Cell Responses Restricted by human leukocyte antigen (HLA)-DRB1 Exist in Natural HIV Infection Virus-specific CD8+ T cells typically recognize infected cells through presentation of processed viral peptides on HLA class I molecules, but class II-restricted responses have been detected in some experimental systems and in the context of CMV vector immunization in a macaque simian immunodeficiency virus (SIV) vaccine model (Hansen et al, 2013)
Summary
Antigen-specific CD8+ T cells are a major defense against invading viruses, killing infected cells harboring non-self proteins. The first step in this process involves T cell receptor (TCR) recognition of virus-derived peptides presented on the surface of infected cells by molecules of the major histocompatibility complex (MHC) or human leukocyte antigen (HLA) in humans. CD8+ T cell responses restricted by MHC class II have been described in approximately a dozen published reports over the past two decades. These responses have been observed in Cd4-deficient mice, where the complete absence of CD4+ T cells led to the unexpected expansion of CD8+ T cells restricted by class II (Matechak et al, 1996; Mizuochi et al, 1988; Pearce et al, 2004; Shimizu and Takeda, 1997; Suzuki et al, 1994; Tyznik et al, 2004), and in mouse models of transplantation (Hirosawa et al, 2011). Reports have described alloreactive CD8+ T cell responses that cross-recognize HLA class I and II (Heemskerk et al, 2001; Rist et al, 2009), indicating that unconventional HLA and TCR interactions may be an important feature of allorecognition
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