Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction

Abstract

In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)-specific CD4(+) T cells but not CD8(+) T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4(+) T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4(+) T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4(+) T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4(+) T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…Moreover, PD-1 blockade seems to reactivate effector T cells through the targeting of certain transcriptional factors (i.e., nuclear factor kappa-light-chainenhancer of activated B cells, interferon regulatory factors 1 and 2, orphan nuclear receptor NR4A1, and B-lymphocyte-induced maturation protein 1) that cause a reengagement of the effector mechanisms in the epigenome of exhausted T cells 59 . CTLA-4 has also been found to have a clear role in multiple chronic infections, including HBV, HCV, and HIV, and its inhibition can increase the function of pathogen-specific T cells 60,61 . Epigenetic and transcriptional mechanisms determine the functional plasticity of T cells to switch between their exhausted and effector states 62 , and so altering the transcriptional landscape-for example, by manipulating transcription-factor and gene-enhancer expression-and epigenetic landscape-for example, by manipulating the activity of histone-modifying methylation or demethylation enzymes, histone acetylases, and DNA demethylases-of adoptively transferred T cells may yield a more specific anti-tumor response than generalized PD-1 and CTLA-4 blockade.…”

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

“…In addition to these inhibitory receptors, it was demonstrated that a variety of other inhibitory receptors were expressed on exhausted CD8 + T cells in chronic virus infections, and the increased levels of expression were critically associated with the severity of infection and the lower functionality of CD8 + T cells (10). Although the precise inhibitory mechanisms of each individual pathway are unclear, some inhibitory receptors, such as Tim-3, LAG-3, and CTLA4, are known to negatively regulate CD8 + T cell function cooperatively with PD-1, because combined blockade of these inhibitory receptors, along with the PD-1/PD-L1 pathway, synergistically improved CD8 + T cell responses (10)(11)(12)(13). Based on the present observations, Ag-specific effector CD8 + T cells in FV-infected mice seemed to be undergoing unusually rapid and extremely severe exhaustion.…”

“…PD-1 has been identified as a major cell-surface inhibitory receptor capable of regulating CD8 + and CD4 + T cell exhaustion in mice, as well as in humans and nonhuman primates (50). Tim-3 and CTLA-4 were recently found to be overexpressed on HIV-and hepatitis C virus-specific CD8 + and CD4 + T cells and to act to suppress effector functions of activated T cells (11)(12)(13)51). Upregulation of LAG-3 was also shown to correlate with the impaired effector functions and exhaustion of CD8 + T cells (10,52,53).…”

“…A recent study using the lymphocytic choriomeningitis virus (LCMV) provided a likely explanation for the relatively limited effect of the PD-1 blockade: exhausted CD8 + T cells are coregulated by multiple inhibitory receptors during chronic infection (10). Thus, targeting the precise inhibitory receptors for blockade (10)(11)(12)(13), the timing and duration of treatment, and combination with additional therapeutic vaccination and/or antiviral drugs (14) must be considered to establish the optimal therapeutic strategy that can improve/restore the function of virus-specific CD8 + T cells without enhancing immunopathology.…”

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

“…Previous reports demonstrated that PD-1 was significantly upregulated on virus-specific CD8 + T cells and that CTLA-4 was upregulated on HIV-specific CD4 + T cells during persistent viral infection; both PD-1 and CTLA-4 could negatively regulate T cell functionality (6,7,15). Similarly to CTLA-4 and PD-1, lymphocyte activation gene-3 (LAG-3), which is a natural high-affinity ligand for MHC class II (MHC II) molecules (16), was shown to play an inhibitory role in regulating T cell immune responses by several studies (17)(18)(19)(20)(21).…”