Volume 25 Issue 1, January 2024

T cells exist in many functional states, and dynamic transitions from one state to another affect the outcome of adoptive T cell therapy. FOXP1 and KLF2 are now identified as transcriptional regulators of the stemness of CD8⁺ CAR-T cells and the bifurcation of stem-like CD8⁺ CAR-T cells into effector and exhausted subsets, respectively.

The use of T cell receptor signatures to track activated spike-specific T cell dynamics between recovery from SARS-CoV-2 infection and subsequent mRNA vaccination shows that vaccination effectively recruits pre-existing memory and new CD8⁺ T cell clonotypes.

Epithelial cells, macrophages and T cells are linked in a previously unknown regulatory circuit. Sensing of interferon-γ triggers antigen presentation by colonic epithelial cells, enabling T cells to lower extracellular ATP levels and reduce inflammation.

Expressing chimeric antigen receptors (CARs) in macrophages has led to promising results in preclinical and clinical work. Now, induced pluripotent stem cells have been combined with a second-generation CAR to achieve macrophage rewiring and to broaden the applicability of the approach to solid malignancies.

BCG vaccination provides protection against unrelated viral infections. The vaccine induces protective integrated organ immunity through biphasic activation of innate and adaptive immune cells.

We describe a system for introducing guide RNAs (gRNAs) to Cas9-expressing hematopoietic stem cells, which are used to generate mice with gene knockouts in the immune system. By using different gRNA-containing vectors and Cas9-expressing mice, we created systems for knockout of single genes or pairs of genes constitutively or inducibly.

Mouse macrophages express specialized genes particular to the organs they inhabit, but whether the same applies in humans is unclear. In human peritoneal fluid, we identified many macrophage phenotypes, including two specialized macrophage types that corresponded to distinct mouse peritoneal macrophages. However, their abundances were markedly different between species.

In this Review, Netea and colleagues summarize the latest research that contributes to our understanding of the pathophysiology of sepsis, and how this contributes to a new treatment approach through personalized immunotherapy.

In this Review, the authors describe the mechanisms that account for the generation and immune recognition of neoantigens that are not derived from DNA mutations, with a special focus on relevance to cancer and autoimmunity.

Pulendran and colleagues delineated the mechanisms underlying the nonspecific antiviral effects exerted by the BCG vaccine against SARS-CoV-2 and reveal a pivotal role for BCG-specific CD4⁺ T cells that produce interferon-γ in imprinting a persistent antiviral innate program in the lung, mediating heterologous viral protection.

Wang and colleagues revealed how oleic acid produced by thymic epithelial cells could affect the developing thymocytes to differentiate into peripheral regulatory T cells.

TCF1⁺ ‘stem-like’ CD4⁺ T cells have a capacity for self-renewal and effector differentiation when required. Here the authors show how these stem-like T cells mediate allograft rejection via the replenishment of their effector differentiation.

Colonna and colleagues show that the transcription factor Aiolos controls chromatin accessibility and histone acetylation at genes linked to the activation of intestinal intraepithelial lymphocytes.

Here, the authors show that combining γ9δ2 TCR-mediated metabolic and co-stimulatory stress targeting by chimeric NKG2D or anti-CD277 co-receptors shapes transcriptomic heterogeneity of engineered T cells and is associated with improved control of solid tumors.

Induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) are being used to make chimeric antigen receptor (CAR) macrophages for immunotherapy. Here the authors design a second-generation macrophage-specific CAR by integrating CD3ζ and toll/IL-1R (TIR) domains resulting in an M1-polarized CAR-iMAC with increased antitumor functions.

Wu and colleagues identify gene networks and transcription factors that control the differentiation of stem-like CD8+ CAR T cells into effector or exhausted CD8⁺ CAR T cells.

Mandal and colleagues report how the chromatin modulator BRWD1 mediates extensive changes in 3D chromatin topology during B cell development by converting static to dynamic cohesin.

Cyster and colleagues show that CD97–CD55 interactions, which trigger Gα₁₃–ARHGEF–Rho cytoskeletal signaling, are needed for proper MZ B cell positioning/retention in the spleen and for optimal antibody responses to T cell-independent antigens.

Randolph and colleagues analyze the immune cells in the human and mouse peritoneum and show that the major populations of serous cavity-resident macrophages in humans and mice represent distinct differentiation stages of an overlapping differentiation program.

Koelle and colleagues use an activation marker-dependent approach to determine the recruitment of TCR by three doses of mRNA vaccination in individuals previously infected with SARS-CoV-2.

Sharpe and colleagues devise a conditional gene deletion model in mice for rapid sequential, combinatorial and lineage-specific interrogation of gene function in hematopoietic cells.