Increased Frequency of CD49b/LAG-3⁺Type 1 Regulatory T Cells in HIV-Infected Individuals

Abstract

In HIV-1 infection elevated serum levels of interferon-α (IFN-α) and interleukin-10 (IL-10) are associated with immune hyperactivation and disease progression. Recently, coexpression of CD49b and LAG-3 was shown to identify Type 1 regulatory T (Tr1) cells, which secrete large amounts of the immunosuppressive cytokine IL-10. We analyzed the frequency of CD49b/LAG-3(+) Tr1 cells in the peripheral blood of HIV-infected individuals at different stages of the disease. We found increased levels of CD49b/LAG-3(+) Tr1 cells as well as IL-10 in HIV patients. With disease progression, Tr1 cells negatively correlate with frequency of plasmacytoid dendritic cells (pDCs), the main producers of IFN-α. However, elevated IL-10 levels could not be ascribed to the CD49b/LAG-3(+)Tr1 cell population. Moreover, we showed in vitro that IFN-α leads to an upregulation of IL-10 as well as CD49b/LAG-3(+) Tr1 cell counts in healthy controls, recapitulating effects observed in vivo during HIV infection. Our results suggest that overexpression of IFN-α during HIV infection drives the generation of CD49b/LAG-3(+) Tr1 cells and the immunosuppressive cytokine IL-10. Furthermore, it remains unclear whether elevated IL-10 levels are beneficial or detrimental in regard to disease progression.

Immune Checkpoints in Viral Infections

“…Under normal physiologic conditions, an increase in Treg cells protects tissues from damage due to excessive immune cell activation and proliferation [103]; however, it also plays a critical role in the immune suppressive reaction that is critical for chronic viral persistence [104,105]. Treg cells from HIV-1-infected patients express significantly higher levels of PD-1 [56,57], TIM-3 [106], CTLA-4 [107], and LAG-3 (Tr1) [58,59] compared with those from healthy individuals. Treg cells partly lose their ability to regulate T-cell function and proliferation during the chronic phase of HIV infection [108].…”

CD4+CD25−LAG3+ regulatory T cells in humoral immunity

“…LAG3 and CD49b are found to correlate with IL‐10 expression in CD4 + T cells from mice treated with a dose escalation strategy for efficient self‐antigen‐specific tolerance induction . In HIV‐infected individuals, the frequency of LAG3 + CD49b + Tr1 cells was increased, as well as serum levels of IL‐10 . Tr1 cells are also shown to play an important role in the prevention and treatment of autoimmune diseases, organ transplantation and chronic inflammatory diseases .…”

Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Effective Immunotherapy Strategy

“…Furthermore, the co-expression of PD-1 and LAG3 decreases levels of the inflammatory cytokines IFN-γ and TNF; however, blockade of LAG3 and PD-1 improved cell proliferation and increased cytokine production in antigen-specific CD8+ TILs ( 46 ). LAG3 is constitutively expressed by a subset of thymus-derived regulatory T cells (Treg cells) and the co-expression of LAG3 and integrin CD49b identified type 1 Treg cells that produce IL-10 ( 47 ). LAG3 is involved in the ITAM inhibitory signaling pathway and inhibits DC maturation.…”