In This Issue

doi:10.4049/jimmunol.1890027

Shaping Thymocyte Selection

Thymocyte development involves a series of selection events that are influenced by interactions with cortical thymic epithelial cells (cTECs). Gene expression in cTECs is shaped by the presence of thymoproteasomes. PSMB11 is a catalytic subunit expressed exclusively in these cTEC proteasomes, and Apavaloaei et al. (p. 966) now examine the role of this protein in regulating cTEC gene expression and thymocyte development. RNA sequence analysis of TEC subsets in wild-type and Psmb11^−/− mice revealed that PSMB11 inhibits WNT signaling and is critical for regulating genes involved in chemokine signaling and cell adhesion. Deletion of PSMB11 causes cTECs to develop a phenotype more similar to medullary TECs, which results in retention of CD8 thymocytes in the thymic cortex, oxidative stress, and eventual apoptosis. CD4 thymocytes also undergo oxidative stress in the absence of Psmb11 but do not undergo apoptosis. Together, these results highlight a role for PSMB11 in regulating the cTEC gene expression program, with a downstream impact on thymocyte development and selection.

Innate Immune Dysfunction in Obese Diabetics

Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen long-term morbidity and mortality from sepsis. Although numerous studies suggest that neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation are reduced in diabetic states, the contribution of these deficits to sepsis is unclear. Using a cecal ligation and puncture (CLP) model of sepsis Frydrych et al. (p. 931) demonstrated higher mortality in mice with diet-induced obesity (DIO) following CLP when compared with lean mice. The enhanced mortality was associated with an inability to eliminate bacteria from the peritoneal cavity. Following CLP, DIO mice had a significant reduction in the number of monocytes in the bone marrow, as well as a decrease in the number of both splenic neutrophils and monocytes, indicating dysfunctional emergency granulopoiesis. Additionally, neutrophils and monocytes from DIO mice showed decreased phagocytic ability and an attenuated capacity to generate ROS after CLP. Consistent with these observations, neutrophils isolated from DIO mice after CLP showed decreased Axl and Mertk levels, both of which are relevant to phagocytosis signaling. Finally, both lean and DIO mice produced very little GM-CSF after sepsis. Administration of GM-CSF to DIO mice improved survival and monocyte functional ability after CLP. Thus, this study demonstrates neutrophil and monocyte defects in obese patients with diabetes and suggests that GM-CSF may be a potential therapeutic option to improve sepsis outcomes in these individuals.

CMV Status Update

Cytomegalovirus can remain dormant for decades in infected individuals, but latent CMV infection may be reactivated in immunosuppressed individuals undergoing allogeneic hematopoietic stem cell transplantation because they lack CMV-specific T cells. Huth et al. (p. 979) use high-resolution TCRβ sequencing to understand the HLA-C–restricted T cell repertoire. In CMV-positive individuals, they confirmed that CMV-specific TCRβ clonotypes were highly abundant within the T cell repertoire. Public TCRβ families specific to CMV epitopes were also more abundant in CMV-positive individuals versus CMV-negative individuals. They validated this CMV-specific TCRβ signature in a larger cohort with known CMV status, and these results indicate that this signature may be useful in assessing CMV-specific T cell immunity in individuals.

TLR–TCR Synergy

Although T cell activation requires Ag recognition through the TCR and engagement of costimulatory molecules, engagement of TLRs can also drive cytokine production. In this issue, Salerno et al. (p. 714) sought to determine if TLR ligands have the capacity to provide costimulatory signals and enhance Ag-driven T cell activation. Activation of CD8⁺ T cells in the presence of TLR2 and TLR7 ligands not only promoted IFN-γ production but also lowered the Ag threshold required for T cell signaling in vitro. The authors demonstrated that costimulation through TLR2 not only increased de novo Ifng mRNA transcription but also synergized with TCR signaling to prolong the half-life of Ifng mRNA, thereby promoting IFN-γ production. Conversely, TLR7 induced only de novo mRNA transcription. Importantly, mRNA stabilization enhanced by TLR2 ligands correlated with enhanced polyfunctional capacity of T cells directed against tumor cells. Thus, TLR2 and TLR7 ligands can provide costimulatory signals to CD8⁺ T cells, but through different mechanisms. These observations may be crucial to optimize TLR ligands as adjuvants to improve the efficacy of vaccines and immunomodulatory therapies.

IL-15 Addiction

Natural killer cells used for adoptive cell therapy are expanded in vitro in the presence of cytokines like IL-2 and IL-15, but normally fail to thrive after withdrawal from these cytokines and transfer into patients. Jacobs et al. (p. 736) now examine the effects of IL-15 withdrawal on NK cell viability. NK cells cultured under high-dose IL-15 and then exposed to a lower dose in vitro showed reduced proliferative capacity and caspase-3 activation, as well as enhanced apoptosis in rapidly dividing cells. In mechanistic studies to understand the apoptotic response, the authors showed that levels of the proapoptotic protein BIM short splice variant increased in NK cells exposed to high levels of IL-15, whereas ratios of the antiapoptotic protein BCL-2 to BIM decreased profoundly upon IL-15 withdrawal. Together, these findings may inform new strategies to culture NK cells in vitro for adoptive cell therapy, rendering them less susceptible to apoptosis after transfer into patients.

Glucocorticoid-Driven IL-10 Is IL-2 Dependent

Glucocorticoids, which are used clinically to treat asthmatics, are known to increase production of IL-10. However, these compounds can also enhance production of IL-17 by PMBCs, a common feature of severe asthma and glucocorticoid-refractory disease. In this issue, Mann et al. (p. 684) sought to better understand the opposing effects of glucocorticoids on IL-10 and IL-17 production. The glucocorticoid dexamethasone significantly increased IL-10 and IL-17 production by human memory CD4⁺ T cells. Notably, a greater fold increase in IL-17 production was observed in cells coproducing IL-10 and Th17-associated cytokines. Although glucocorticoids are known to dampen T cell proliferation, both IL-10⁺ and IL-17⁺IL-10⁺ cells were refractory to this effect, and this was associated with a decrease in cell surface expression of the IL-2 receptor components CD25 and CD122. Interestingly, cells upregulating CD25 proceeded into cell division in the presence of dexamethasone. Moreover, the percentage of CD25⁺ cells was higher in IL-10⁺ populations, suggesting that IL-2 can independently regulate IL-10. Consistent with this, high doses of IL-2, both alone and in combination with dexamethasone, increased only the proportion of IL-10⁺ T cells. Therefore, this study predicts that IL-2 may be key for optimizing glucocorticoid clinical therapies in asthma treatments.