Unconventional T cells in chronic disease and as targets of therapy

The 1960s heralded an era of investigation into the division of labor between B cell and antibody-based humoral immunity and thymus-derived T-cell-based cellular immunity [1, 2]. The subsequent advent of monoclonal antibody technology [3], advances in flow cytometry [4], gene cloning, and molecular biology [5–7] provided unprecedented mechanistic insights into the basic properties of T- and B-cell antigen recognition, how receptor diversity is generated, and how tolerance to self is established and maintained. At the same time, they revealed further divisions of labor, particularly within the T-cell lineage, outlining subclasses of T cells such as MHC Class I restricted, CD8-positive cytotoxic T cells and MHC Class II restricted, CD4-positive, helper T cells and various subsets therein including Th1 T cells to promote anti-viral responses, Th2 T cells to promote anti-parasitic responses and an emerging panoply of additional subsets with ever greater subtlety in anti-pathogen function [8, 9]. In parallel to this Immunological Renaissance in adaptive immunity that defined ever greater complexity and divisions of labor, was an equally profound series of discoveries in innate immunity. Discrete subsets and origins of macrophages, neutrophils, dendritic cells (DCs), mast cells, and eosinophils were reshaping the way we think about tissue-specific inflammatory, repair, and immune responses orchestrated during adult life but also during development [10, 11]. Importantly, and particularly with regard to this compendium of articles, the lines between adaptive and innate immunity progressively become blurred. On the innate side of the equation, natural killer (NK) cells, plasmacytoid DCs, and more recently, innate lymphoid cells (ILCs) were found to have strikingly similar functional capabilities to cells of the adaptive immune system and yet lack the requisite T- and B-cell receptors to provide antigen specificity. On the adaptive side of the equation, gamma delta (γδ) T cells, B1 B cells, NK T cells, and mucosal-associated innate T (MAIT) cells were each shown to possess antigen-specific receptors but with a more limited repertoire, in many cases with lower affinity and broader specificity, and often with limited dependency on the classical MHC I and II molecules for the T lineage cells. Because many of these cells tended to arise prominently during early pre- and post-natal development, a temporal window that often recapitulates evolution, many speculated that these cells simply represent evolutionary relics of adaptive immunity. But with greater insights provided by single sequencing technologies, elegant gene knockout technology, and crucially, better experimental models for evaluating the subtleties of immune function, it has become clear that these cells, in fact, have been maintained throughout vertebrate evolution because they serve critical functions in specialized situations that can only be revealed through appropriate experimental models. Indeed, it is increasingly accepted that in neonatal life, these cells play an essential role by providing protection from the first wave of pathogens we encounter and buying us a critical window of opportunity to sculpt the more exquisitely specific immunity provided by the B2 and alpha-beta (αβ) T cells and the requisite accessory cells and secondary lymphoid tissues. Contemporaneously with the identification of the aforementioned innate T-cell subsets came the characterization of T regulatory (Treg) cells as an atypical T-cell subset with critical roles in restraining autoreactive and hyperactive T-cell responses through an emerging series of mechanisms [12]. In essence, the function of these cells is the polar opposite of conventional T cells, and their therapeutic use in tolerance induction, transplantation biology, and suppression of autoimmunity has become one of the hottest topics in clinical immunology. Naturally, the recognition of unconventional T-cell subsets and their biological influence in development, homeostasis, and disease gave rise to an emerging field of interest to the wider community. In 2022, the Canadian Society for Immunology (CSI) sponsored “Unconventional T cells in Chronic Disease and as Targets of Therapy” as guest symposium at the annual FOCIS Conference. The goal of this meeting was to highlight new data from Canadian research groups investigating unconventional T cells and to stimulate debate and discussion on their function, their role disease and the potential therapeutic uses of these, often overlooked, cells. The series of review articles in this issue of Clinical & Experimental Immunology are a byproduct of that symposium and contains articles from many of the presenters as well as other leaders in this field. While it is admittedly far from comprehensive, it does provide a fascinating series of vignettes on several of these less-widely studied cells and important insights into their unusual properties. With regard to Treg cell biology, reviews from Valentini et al. [13] and Golzari-Sorkheh et al. [14] provide insights into the normal development and function of Treg cells, transcriptional regulation, mechanistic modes of action, the various roles they play in disease when their function is disrupted and their clinical promise as the basis for novel therapeutics. Joannou et al. [15] review non-classical MHC-restricted CDαα intraepithelial lymphocytes (IELs), a fascinating unconventional T-cell subset that develops in the thymus in a process quite distinct from conventional T cells and relies on agonist selection. Like Tregs, this distinct subset of cells appears to have a key role in tissue homeostasis and creating an immunosuppressive environment in the intestine. Wang et al. [16] provide a comprehensive review of MAIT cells highlighting their much more limited repertoire and restriction to the non-classical MHC molecule, MR1. Hackstein et al. [17].provide a broader overview of the array of innate T cell subsets including MAIT cells, γδ T cells, iNKT cells, but also further subsets of these various lineages that behave more like adaptive cells, further blurring the distinction between innate and adaptive immunity. Finally, Jan-Abu et al. [18] and Mak et al. [19] provide overviews of what many would fail to consider T cells; the innate lymphoid cells (ILCs). While many would consider these inappropriate for a compendium on “unconventional T cells” due to their lack of expression of a cell surface TCR, the choice, we feel, is quite judicious for a number of reasons. These cells show striking similarities in terms of their functional capabilities to TCR + T cells and importantly, despite early reports suggesting that they originate from committed bone marrow precursors, emerging data suggest that a significant proportion of these cells are thymus-derived and have evidence of faulty T-cell receptor rearrangements placing them within the bounds of the historically defined “thymus-derived” lymphocytes [20]. Semantics aside, functionally, these cells exhibit fascinating parallels to both conventional and unconventional TCR + cells and yet when evaluated in discrete disease scenarios show unique and non-redundant functions as evidenced by their roles in allergy and intestinal inflammatory disease. The review by Mak and colleagues provides a completely new evaluation of the role of ILCs in transplantation and highlights opportunities for their manipulation as next generation therapeutics. From these points of view, ILCs represent one more element in a continuum from innate to adaptive immunity and appropriately are included here. Coming back to the original question of whether unconventional and innate T cells represent an evolutionary relic on the road to emergence of the exquisitely antigen-specific conventional T cells, the articles in this compendium answers this with a resounding “No!”. While in many cases, they exhibit a degree of functional overlap, these articles also highlight specific scenarios where they are indispensable arguing that they have been conserved due to the selective advantage they provide for survival. We hope this compendium serves as a vital primer for further investigation into these fascinating subsets. An AllerGen Network Centre of Excellence and CIHR Frederick Banting & Charles Best Canada Graduate Scholarship-Master’s Program (CGS-M) Scholarship supported SBS. This work was funded by Canadian Institutes of Health Research (CIHR) project grant numbers PJT-148681 and PJT-156235 and CMI2 Team Grant MRT-168044 to KMM. None declared.

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