Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Abstract

Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

“…Emerging data suggest that kynurenine may play a more direct role than the consumption of tryptophan catabolized by IDO in immune regulation and responses in tumor microenvironment . Kynurenine can activate transcription factor aryl hydrocarbon receptor (AhR).…”

“…32 Emerging data suggest that kynurenine may play a more direct role than the consumption of tryptophan catabolized by IDO in immune regulation and responses in tumor microenvironment. [33][34][35] Kynurenine can activate transcription factor aryl hydrocarbon receptor (AhR). The activation of AhR induces a number of immunosuppressive phenotypes including the generation of immunetolerant dendritic cells and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…In fact, kynurenine-a metabolite of L-tryptophan-has been shown to reduce memory CD4 T cell survival. 151 Studies by our group and others have shown that Arg1-expressing tumor-associated myeloid cells exhibit suppressive activity against T cells. 152,153 Lactic acid, a by-product of tumor metabolism, has been found to suppress T cell proliferation and production of cytokines.…”

“…These enzymes are highly expressed by tumor cells and/or myeloid cells within the TME and can cause T cell suppression. In fact, kynurenine—a metabolite of L‐tryptophan—has been shown to reduce memory CD4 T cell survival . Studies by our group and others have shown that Arg1‐expressing tumor‐associated myeloid cells exhibit suppressive activity against T cells .…”

Pregnancy Gestation Impacts on HIV-1-Specific Granzyme B Response and Central Memory CD4 T Cells

“…CD4 T-cell counts in HIV-1 positive women decrease in pregnancy before restoration post-partum, and under ART pregnancy is not associated with HIV-1 disease progression (25,26). In early HIV-1 infection IL-2 signaling is compromised which impacts the development and maintenance of Tcell memory populations, while other work suggests the degranulation capacity of CD8 cytotoxic T-cells is disrupted, and CD4 and CD8 T-cell subset frequencies are skewed even under ART (8,(27)(28)(29)(30). Memory CD4 T-cell frequency is increased in HIV-1 positive pregnant and non-pregnant women compared to their HIV-1 negative counterparts, although detailed changes in T-cell memory subsets have not been explored between nonpregnant and pregnant HIV-1 positive women under ART (31).…”