Interleukin-21 Induces Short-Lived Effector CD8 ⁺ T Cells but Does Not Inhibit Their Exhaustion after Mycobacterium bovis BCG Infection in Mice

Abstract

Interleukin 21 (IL-21) is a pleiotropic common cytokine receptor γ chain cytokine that promotes the effector functions of NK cells and CD8 T cells and inhibits CD8 T cell exhaustion during chronic infection. We found that the absolute number of short-lived effector CD8 T cells (SLECs) (KLRG1 CD127) decreased significantly in IL-21 receptor-deficient (IL-21R) mice during bacillus Calmette-Guérin (BCG) infection. Early effector CD8 T cells (EECs) (KLRG1 CD127) were normally generated in IL-21R mice after infection. Exhausted CD8 T cells (PD-1 KLRG1) were also normally generated in IL-21R mice after infection. Mixed bone marrow (BM) chimera and transfer experiments showed that IL-21R on CD8 T cells was essential for the proliferation of EECs, allowing them to differentiate into SLECs after BCG infection. On the other hand, the number of SLECs increased significantly after infection with recombinant BCG (rBCG) that secreted an antigen 85B (Ag85B)-IL-21 fusion protein (rBCG-Ag85B-IL-21), but the number of exhausted CD8 T cells did not change after rBCG-Ag85B-IL-21 infection. These results suggest that IL-21 signaling drives the differentiation of SLECs from EECs but does not inhibit the exhaustion of CD8 T cells following BCG infection in mice.

Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

“…During the course of a chronic viral infection or under IL-2-deprived conditions, IL-21R signaling is critical for preventing CD8 + Tcell exhaustion 19,20 . In acute viral infections, IL-21R signaling is essential for the proliferation and survival of activated CD8 + T cells as well as the generation of long-lived memory cells 21,22,23 . In these models, IL-21R can activate the STAT1/STAT3 signaling pathways, which subsequently upregulate pro-survival factors BCL-2 and BCL-XL and downregulate TRAIL 22,23 .…”

“…In acute viral infections, IL-21R signaling is essential for the proliferation and survival of activated CD8 + T cells as well as the generation of long-lived memory cells 21,22,23 . However, the function of IL-21R signaling in cancer is controversial and not completely understood 24,25,26,27,28 .…”

Dissociating STAT4 and STAT5 Signaling Inhibitory Functions of SOCS3: Effects on CD8 T Cell Responses

“…Signaling by IL-21, IFN-α, and presumably other JAK1-dependent pathways is restored by the mutant SOCS3. Although it is not clear which of these pathways would prevent differentiation of memory precursor cells, type I IFN has been shown to promote effector cell differentiation ( 27 , 28 ), and IL-21 can promote effector cell differentiation in a context-dependent manner ( 29 , 34 , 35 ). The absence of memory precursor skewing during suppression of IL-12 signaling was surprising, considering a previous study showing that IL-12–deficient mice infected with LM-OVA develop larger memory CD8 T cell populations ( 36 ).…”

RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

“…This was postulated to be caused by IL-21 being important for both, CD8+ T-cell priming, as well as inhibiting the expression of the exhaustion markers programmed death 1 (PD-1) and mucin domain-containing protein 3 (TIM-3) [92]. However, a different set of mice experiments could not confirm the link of IL-21 preventing PD-1 expression, but did show that IL-21 played a role in CD8+ T-cell differentiation and proliferation upon BCG challenge [103]. IL-21 has been found to promote NK activation in humans, leading to enhanced production of IFNγ, perforin, granzyme B, and granulysin.…”