Interleukin (IL)-2 and IL-21 dichotomously shape CD8 ⁺ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (T _SCM ) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2–induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1 . While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21–induced metabolism but caused major transcriptomic changes, including the suppression of IL-21–induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of T _SCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.

Significance: Superenhancers regulate the expression of genes that specify cell type-specific development, but little is known regarding their function and regulation in vivo. Here, we study the cytokines IL-2 and IL-21, which critically control the immune response. These cytokines induce the binding of transcription factors STAT5 and STAT3, respectively, at superenhancers in a cytokine- and gene-specific manner. STAT5-bound superenhancers regulate genes highly induced by IL-2, with STAT5 mediating chromatin looping within such genes, including Il2ra , which mediates responsiveness to IL-2. By deleting three STAT5 binding sites that mediate IL-2–induced chromatin looping at the Il2ra locus, we demonstrate that superenhancer elements cooperatively control gene expression. Overall, we elucidate cytokine-dependent superenhancer function in general and provide detailed analysis of the Il2ra superenhancer.

Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on the sharing of a receptor component, the common cytokine receptor γ chain, γc, which is encoded by the gene mutated in humans with X-linked severe combined immunodeficiency (XSCID). Together, these cytokines play critical roles in lymphoid development, differentiation, growth, and survival as well as mediating effector function. Here, we provide an overview of the main actions of members of this cytokine family but then primarily focus on IL-2 and IL-21, discussing their dynamic interplay and contributions to a fine-tuned immune response. Moreover, we discuss the therapeutic utility of modulating their actions, particularly for autoimmunity and cancer.

Background: In the Southeastern United States, the 2022 mpox outbreak disproportionately impacted people who are black and people with HIV (PWH). Methods: We analyzed a cohort of 395 individuals diagnosed with mpox across 3 health care systems in Atlanta, Georgia between 1 June 2022 and 7 October 2022. We present demographic and clinical characteristics and use multivariable logistic regression analyses to evaluate the association between HIV status and severe mpox (per the US Centers for Disease Control and Prevention definition) and, among PWH, the associations between CD4+ T-cell count and HIV load with severe mpox. Results: Of 395 people diagnosed with mpox, 384 (97.2%) were cisgender men, 335 (84.8%) identified as black, and 324 (82.0%) were PWH. Of 257 PWH with a known HIV load, 90 (35.0%) had > 200 copies/mL. Severe mpox occurred in 77 (19.5%) individuals and there was 1 (0.3%) death. Tecovirimat was prescribed to 112 (28.4%) people, including 56 (72.7%) people with severe mpox. In the multivariable analysis of the total population, PWH had 2.52 times higher odds of severe mpox (95% confidence interval [CI], 1.01–6.27) compared with people without HIV. In the multivariable analysis of PWH, individuals with HIV load > 200 copies/mL had 2.10 (95% CI, 1.00–4.39) times higher odds of severe mpox than PWH who were virologically suppressed. Lower CD4+ T-cell count showed a significant univariate association with severe mpox but was not found to be significantly associated with severe mpox in multivariable analysis. Conclusions: PWH with nonsuppressed HIV loads had more mpox complications, hospitalizations, and protracted disease courses than people without HIV or PWH with suppressed viral loads. PWH with nonsuppressed HIV loads who are diagnosed with mpox warrant particularly aggressive monitoring and treatment.

Importance: Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to people with HIV (PWH) with mpox during the 2022 mpox epidemic, particularly PWH with low CD4⁺ T-cell counts or severe mpox clinical manifestations.Objective: To evaluate if PWH with mpox who were treated with tecovirimat within 7 days of symptom onset were less likely to have mpox disease progression.Design, Setting, and Participants: This cohort study included PWH diagnosed with mpox at 4 hospitals in Atlanta, Georgia, between June 1 and October 7, 2022. Patients were grouped according to whether they were treated with tecovirimat within 7 days of mpox symptom onset (early tecovirimat cohort) or they did not receive tecovirimat or received the drug 7 or more days after symptom onset (late or no tecovirimat cohort). Multivariable logistic regression models were used to identify factors associated with progression of mpox disease. The 2 cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.Exposures: Treatment with tecovirimat within 7 days of mpox symptom onset.Main Outcome and Measures: Progression of mpox disease, defined as the development of at least 1 severe mpox criterion established by the US Centers for Disease Control and Prevention, after symptom day 7.Results: After propensity score matching, a total of 112 PWH were included in the analysis; 56 received tecovirimat within 7 days of mpox symptom onset (early tecovirimat group) and 56 were either treated later or did not receive tecovirimat (late or no tecovirimat group). In the early tecovirimat group, the median (IQR) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black individuals, and 10 (17.9%) were individuals of other races (American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or White) or unknown race. In the late or no tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black individuals, and 7 (12.5%) were individuals of other races or unknown race. Mpox disease progression occurred in 3 PWH (5.4%) in the early tecovirimat group and in 15 PWH (26.8%) in the late or no tecovirimat group (paired odds ratio, 13.00 [95% CI, 1.71-99.40]; P = .002).Conclusion and Relevance: Results of this cohort study support starting tecovirimat in all PWH as soon as an mpox diagnosis is suspected. Additional research is warranted to confirm these findings.

Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4⁺ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8⁺ T-cell primary responses remains controversial and its role in memory CD8⁺ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral systems. Interestingly, TSLP limited the primary CD8⁺ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8⁺ T cells generated after influenza infection. However, TSLP inhibited memory CD8⁺ T-cell responses to secondary viral infection with influenza or acute systemic LCMV infection. These data reveal a previously unappreciated role for TSLP on recall CD8⁺ T-cell responses in response to viral infection, findings with potential translational implications.