CD8+ T cells become functionally impaired or “exhausted” in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)–15 production during LCMV clone 13 chronic infection. Muscle-specific ablation of Il15 enhanced the CD8+ T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8+CD103+ muscle-infiltrating lymphocytes (MILs). MILs resided in a less inflamed microenvironment, expressed more T cell factor 1 (Tcf1), and had higher proliferative potential than splenic T cells. MILs differentiated into functional effector T cells after reentering lymphoid tissues. Increasing muscle mass via muscle-specific inhibition of TGFβ signaling enhanced IL-15 production and antiviral CD8+ T cell responses. We conclude that skeletal muscle antagonizes T cell exhaustion by protecting T cell proliferative potential from inflammation and replenishing the effector T cell progeny pool in lymphoid organs.
Highlights d CD8 + T cell function and survival is impaired in HSAN-I patients with SPTLC2 mutation d Mouse CD8 + T cells require SPTLC2 to protect against viral infections d SPTLC2-mediated sphingolipid synthesis prevents mTORC1 hyperactivation and cell death d Sphingolipid supplementation restores SPTLC2-deficient CD8 + T cell effector function
T cells become functionally exhausted in tumors, limiting T cell–based immunotherapies. Although several transcription factors regulating the exhausted T (T
ex
) cell differentiation are known, comparatively little is known about the regulators of T
ex
cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T
ex
cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16
+
CD8
+
tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression.
Rgs16
deficiency inhibited CD8
+
T cell apoptosis and promoted antitumor effector functions of CD8
+
T cells. Furthermore,
Rgs16
deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8
+
T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation.
Rgs16
deficiency enhanced antitumor CD8
+
TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of
Rgs16
-deficient CD8
+
T cells.
RGS16
mRNA expression levels in CD8
+
TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as
SELL
,
TCF7
, and
IL7R
, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of T
ex
cell survival in tumors and has implications for improving T cell–based immunotherapies.
While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1 + IL-7Rα − CD62L − terminal effector memory CD8 + T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8 + T cell pool. Our findings identify Treg cells as an essential IL-15 source maintaining tTEM cells and suggest that Treg cells promote the diversity of immunological memory.
In noncancerous tissues, neighboring cells coexist in metabolic harmony. This metabolic harmony is disrupted in cancerous tissues, often accompanied by genetic mutations. Tumor cells fundamentally change the metabolite profiles in the tumor microenvironment to favor their own growth. In this review, we will discuss several examples in which genetic mutations reprogram tumor cell metabolic pathways, leading to the consumption of essential nutrients in the tumor microenvironment, production of toxic byproducts, and suppression of antitumor immune cell metabolic fitness and tumor-killing function. Finally, we will briefly discuss how immune checkpoint blockade overcomes the metabolic suppression of tumor-infiltrating immune cells.Additional Supporting Information may be found in the online version of this article.
Memory CD8+ T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8+ T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody‐mediated activation of memory CD8+ T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell‐mediated cytotoxicity and promoted effector cytokine production in a glucose‐ and glutamine‐dependent manner. Furthermore, pretreatment of memory CD8+ T cells with an agonistic anti‐CD8 antibody enhanced their tumoricidal activity in vitro and in vivo. From these studies, we conclude that CD8 agonism activates glucose and glutamine metabolism in memory T cells and enhances the efficacy of memory T cell‐based cancer immunotherapy.
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