bims-maitce 2023-12-24 papers

Issue of 2023–12–24
three papers selected by
Andy E. Hogan, Maynooth University

J Exp Med. 2024 Feb 05. pii: e20231487. [Epub ahead of print]221(2):

A conserved transcriptional program for MAIT cells across mammalian evolution.

Mucosal-associated invariant T (MAIT) cells harbor evolutionarily conserved TCRs, suggesting important functions. As human and mouse MAIT functional programs appear distinct, the evolutionarily conserved MAIT functional features remain unidentified. Using species-specific tetramers coupled to single-cell RNA sequencing, we characterized MAIT cell development in six species spanning 110 million years of evolution. Cross-species analyses revealed conserved transcriptional events underlying MAIT cell maturation, marked by ZBTB16 induction in all species. MAIT cells in human, sheep, cattle, and opossum acquired a shared type-1/17 transcriptional program, reflecting ancestral features. This program was also acquired by human iNKT cells, indicating common differentiation for innate-like T cells. Distinct type-1 and type-17 MAIT subsets developed in rodents, including pet mice and genetically diverse mouse strains. However, MAIT cells further matured in mouse intestines to acquire a remarkably conserved program characterized by concomitant expression of type-1, type-17, cytotoxicity, and tissue-repair genes. Altogether, the study provides a unifying view of the transcriptional features of innate-like T cells across evolution.

DOI: https://doi.org/10.1084/jem.20231487

J Immunol. 2023 Dec 20. pii: ji2300639. [Epub ahead of print]

Dynamic MAIT Cell Recovery after Severe COVID-19 Is Transient with Signs of Heterogeneous Functional Anomalies.

Karolinska COVID-19 Study Group

Mucosal-associated invariant T (MAIT) cells are an abundant population of unconventional T cells in humans and play important roles in immune defense against microbial infections. Severe COVID-19 is associated with strong activation of MAIT cells and loss of these cells from circulation. In the present study, we investigated the capacity of MAIT cells to recover after severe COVID-19. In longitudinal paired analysis, MAIT cells initially rebounded numerically and phenotypically in most patients at 4 mo postrelease from the hospital. However, the rebounding MAIT cells displayed signs of persistent activation with elevated expression of CD69, CD38, and HLA-DR. Although MAIT cell function was restored in many patients, a subgroup displayed a predominantly PD-1high functionally impaired MAIT cell pool. This profile was associated with poor expression of IFN-γ and granzyme B in response to IL-12+IL-18 and low levels of polyfunctionality. Unexpectedly, although the overall T cell counts recovered, normalization of the MAIT cell pool failed at 9-mo follow-up, with a clear decline in MAIT cell numbers and a further increase in PD-1 levels. Together, these results indicate an initial transient period of inconsistent recovery of MAIT cells that is not sustained and eventually fails. Persisting MAIT cell impairment in previously hospitalized patients with COVID-19 may have consequences for antimicrobial immunity and inflammation and could potentially contribute to post-COVID-19 health problems.

DOI: https://doi.org/10.4049/jimmunol.2300639

bioRxiv. 2023 Dec 08. pii: 2023.12.07.570707. [Epub ahead of print]

Unraveling the Phenotypic States of Human innate-like T Cells: Comparative Insights with Conventional T Cells and Mouse Models.

Liyen Loh, Salomé Carcy, Harsha S Krovi, Joanne Domenico, Andrea Spengler, Yong Lin, Joshua Torres, William Palmer, Paul J Norman, Matthew Stone, Tonya Brunetti, Hannah V Meyer, Laurent Gapin.

The "innate-like" T cell compartment, known as T inn , represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity, having the ability to mount rapid responses following activation. In mice, this ability is acquired during thymic development. We explored the transcriptional landscape of T inn compared to conventional T cells (T conv ) in the human thymus and blood using single cell RNA sequencing and flow cytometry. We reveal that in human blood, the majority of T inn cells, including iNKT, MAIT, and Vδ2 + Vγ9 + T cells, share an effector program characterized by the expression of unique chemokine and cytokine receptors, and cytotoxic molecules. This program is driven by specific transcription factors, distinct from those governing T conv cells. Conversely, only a fraction of thymic T inn cells displays an effector phenotype, while others share transcriptional features with developing T conv cells, indicating potential divergent developmental pathways. Unlike the mouse, human T inn cells do not differentiate into multiple effector subsets but develop a mixed type I/type III effector potential. To conduct a comprehensive cross-species analysis, we constructed a murine T inn developmental atlas and uncovered additional species-specific distinctions, including the absence of type II T inn cells in humans, which implies distinct immune regulatory mechanisms across species. The study provides insights into the development and functionality of T inn cells, emphasizing their role in immune responses and their potential as targets for therapeutic interventions.

DOI: https://doi.org/10.1101/2023.12.07.570707