Volume 22 Issue 8, August 2021

Mentors are essential for sustaining the physician scientist workforce, but they cannot do it alone.

Different kinds of mentorship provide avenues for researchers to support the development of a more diverse and inclusive science workforce.

New reports provide further insight into the role of the transcription factor BATF in pivoting the differentiation of CD8⁺ T cells away from T cell exhaustion and facilitating the transition of these cells into potent effectors.

Following clearance of chronic infections, virus-specific CD8⁺ T cells recover a subset of memory-related transcriptome features. Yet their unique open chromatin landscape largely reflects an exhausted or dysfunctional state, limiting their protective memory potential.

By engaging Toll-like receptor 2, translationally controlled tumor protein (TCTP) released from necrotic tumor cells can switch on an immunosuppressive network of monocytic and polymorphonuclear myeloid-derived suppressor cells to block antitumor immunity.

Lung fibroblastic stromal cells support inflating memory CD8⁺ T cells after vaccination with an adenovirus vector through the creation of organized lymphoid structures that support the metabolic fitness of these expanded antigen-specific T cells.

Meta-analysis of single-cell RNA sequencing datasets identifies core fibroblasts present in all organs that may give rise to more specialized organ-specific subtypes.

Cell death in the context of cancer therapies is often associated with immunogenicity. Taniguchi and colleagues instead find that release of the cellular protein TCTP following cell death triggers an immunosuppressive pathway in the tumor microenvironment.

Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and the antigenically related Zika virus (ZIKV). Gao and colleagues designed a ZIKV vaccine that induced sterilizing immunity and fetal protection in mice challenged with ZIKV and did not induce ADE following subsequent DENV infection.

The transcription factor ThPOK is critical for homeostasis and differentiation of mature helper T cells. Here, Kappes and colleagues describe a ThPOK-mediated positive autoregulatory loop that is crucial for tissue-specific T_reg cell differentiation, maintenance of intestinal T_reg cell integrity and conversion of these cells into CD4⁺ intraepithelial lymphocytes.

Chronic antigen stimulation leads to CD8⁺ T cell exhaustion, which is mediated by persistent activation of the transcription factor NFAT in the absence of AP-1. Seo, González-Avalos and colleagues show that overexpressed BATF cooperates with IRF4 to counteract NFAT-induced exhaustion and promote better tumor control by CAR T cells in mouse models.

Distinct subsets of effector CD8⁺ T cells can arise in chronically infected mice. Cui and colleagues examine the epigenetic trajectory of TCF-1⁺Ly108⁺ ‘stem-like’ progenitor cells differentiating into CX₃CR1⁺ cytolytic effector CD8⁺ T cells in LCMV-infected mice. Single-cell transcriptomic and ATAC-seq analyses reveal that this progression requires the transcription factors T-bet and BATF.

Wherry and colleagues examine whether exhausted T cells (T_EX) can differentiate into functional memory T cells (T_MEM) when chronic antigen is withdrawn. Using the chronic LCMV infection mouse model, they show that ‘recovering’ T_EX cells (REC-T_EX) only partially recover immunophenotypic and functional characteristics of T_MEM cells. The epigenomic status of REC-T_EX cells more closely resembles that of T_EX cells, and, upon rechallenge, the REC-T_EX cells were still compromised in their ability to respond to virus.

The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8⁺ T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen.

Lauer and colleagues examine CD8⁺ T cells following cure of human hepatitis C virus (HCV) infection. CD8⁺ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.

Ludewig and colleagues show that adenovirus immunization fosters the formation of pulmonary immune-stimulating niches underpinned by fibroblastic stromal cells that maintain ‘inflating’ memory CD8⁺ T cells through the provision of interleukin-33.

Vijayanand and colleagues show highly suppressive CD4⁺CTLA-4⁺PD-1⁺ follicular regulatory T (T_FR) cells reside within tumor microenvironments. Depleting T_FR cells or blocking their activity with CTLA-4-depleting antibodies before anti-PD-1 checkpoint blockade therapy improved the efficacy of anti-PD-1 treatment in mouse tumor models and was also associated with better survival outcomes in a large cohort of patients with melanoma.