Protective HIV-specific CD8+ T cells evade Treg cell suppression

Abstract

Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8+ T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLAB*57 allele groups do not. Here we show that CD8+ T cells restricted by 'protective' HLA allele groups are not suppressed by Tref cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8+ T cells to Tref cell–mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27– and HLA-B*57–restricted effectors also evade Tref cell–mediated suppression by directly killing Tref cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.

T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response

“…Like other Tim members, Tim-3 is one of the type I membrane proteins, which share a characteristic IgV, mucin, transmembrane, and cytoplasmic domain structure. Tim-3 has received much attention because its dysregulation has been linked to many clinical diseases (20)(21)(22)(23). However, it is not known whether Tim-3 plays a role in sepsis, a fatal condition that is the leading cause of death in intensive care units (5,26).…”

“…Because of its critical roles in both innate and adaptive immune regulation, Tim-3 dysregulation has been correlated with the pathogenesis of many clinical diseases. For example, downregulation of Tim-3 is associated with enhanced T effector cell function in autoimmune diseases, such as multiple sclerosis (20) and autoimmune hepatitis (21), whereas its overexpression on T cells correlates with T cell paralysis in patients with tumors or chronic viral infection (22,23). The above data show that the Tim-3 pathway is actively involved in maintaining immune homeostasis in vivo, but the underlying mechanisms by which it regulates immune responses, especially the innate immune response, remain unclear.…”

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…Several mechanisms are thought to be responsible for the apparent failure of autologous cytotoxic T lymphocytes (CTLs) to clear reactivated cells in HIV-infected individuals: HIV evolution prior to ART quickly selects for CTL escape mutations; [17][18][19] HIV Nef mediates downregulation of major histocompatibility complex class I (MHC-I), 20,21 protecting HIV-infected cells from T cell receptor (TCR)-dependent CTL killing; and HIV-specific CTL responses may be limited by exhaustion 22,23 or peripheral immune tolerance. 24,25 Over the last decade, major advances have been made in engineering human T cells via introduction of chimeric antigen receptors (CARs) to enable specific lysis of pathogenic targets. [26][27][28][29] Because CAR T cell activity is MHC-independent, potent, and enforced by expression of an engineered gene cassette, anti-HIV CAR T cells might overcome the limitations of autologous CTLs.…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…In contrast to other effector CD4þ T cell subsets, Tregs preserve their suppressive capacity despite HIV-1 infection [162]. HICs appear to maintain similar or lower levels of Tregs than do healthy individuals [162][163][164][165], and their CD8þ T cells may evade Treg-mediated suppression [166]. This mitigated regulatory response in HICs may help to maintain a robust and efficient T cell response but may also explain the relatively high immune activation observed in these individuals [163], which is associated with some loss of CD4þ T cells (see §6).…”