bims-aditis 2022-04-10 papers

Issue of 2022–04–10
seven papers selected by
Matthew C. Sinton, University of Glasgow

J Invest Dermatol. 2022 Apr 01. pii: S0022-202X(22)00259-7. [Epub ahead of print]

+Vγ2+ γδ T cells in the presence of anti-CD40L control surgical inflammation and promote skin allograft survival.

Shilpi Giri, Heikrujam Thoihen Meitei, Amrita Mishra, Girdhari Lal.

Gamma-delta (γδ) T cells represent a small fraction of total T cells in the body and do not use classical polymorphic MHC-loaded peptides for mounting an immune response. The importance of effector and regulatory function of γδ T cells in infections, autoimmunity, and tumor models are well characterized. In the present study, we investigated the mechanistic role of γδ T cells in costimulatory blockade-induced transplantation tolerance. We used donor-specific transfusion (DST) and anti-CD40L treatment in C57BL/6 mice to induce tolerance to BALB/c skin allografts. We show that depletion of γδ T cells, specifically Vγ2+ γδ T cells, led to the acute rejection of skin allografts despite tolerogen treatment. Tolerogen treatment promoted CD39+Vγ2+ γδ T cells and suppressed IFN-γ-producing Vγ2+ γδ T cells in the spleen and allografts. Vγ2+ γδ T cells isolated from tolerized mice suppress the Th1 cell differentiation. Adoptive transfer of these regulatory Vγ2+ γδ T cells prolonged the survival of allografts in an untreated recipient and TCRδ-/- mice. Together, our data show that the Vγ2+ subset promotes costimulatory blockade-induced survival of skin allografts, and tolerogenic Vγ2+ T cells can be used as an adoptive cellular therapy to promote survival of allografts.

Keywords: CD40L; costimulatory blockade; gamma-delta T cells; tolerance; transplantation

DOI: https://doi.org/10.1016/j.jid.2022.03.016

J Immunol. 2022 Apr 08. pii: ji2100360. [Epub ahead of print]

γδ Thymocyte Maturation and Emigration in Adult Mice.

Kevin Joannou, Dominic P Golec, Haiguang Wang, Laura M Henao-Caviedes, Julia F May, Rees G Kelly, Rigel Chan, Stephen C Jameson, Troy A Baldwin.

Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional γδ T cell subsets are generated in adults. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived γδ thymocytes in mice. In the Rag2pGFP model, immature (CD24+) γδ thymocytes expressed high levels of GFP whereas only a minority of mature (CD24-) γδ thymocytes were GFP+ Similarly, most peripheral GFP+ γδ T cells were immature. Analysis of γδ recent thymic emigrants (RTEs) indicated that most γδ T cell RTEs were CD24+ and GFP+, and adoptive transfer experiments demonstrated that immature γδ thymocytes can mature outside the thymus. Mature γδ T cells largely did not recirculate to the thymus from the periphery; rather, a population of mature γδ thymocytes that produced IFN-γ or IL-17 remained resident in the thymus for at least 60 d. These data support the existence of two populations of γδ T cell RTEs in adult mice: a majority subset that is immature and matures in the periphery after thymic emigration, and a minority subset that completes maturation within the thymus prior to emigration. Additionally, we identified a heterogeneous population of resident γδ thymocytes of unknown functional importance. Collectively, these data shed light on the generation of the γδ T cell compartment in adult mice.

DOI: https://doi.org/10.4049/jimmunol.2100360

Immunometabolism. 2022 ;pii: e220007. [Epub ahead of print]4(2):

Effects of PD-1 Signaling on Immunometabolic Reprogramming.

Vassiliki A Boussiotis, Nikolaos Patsoukis.

Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in several activated immune cells and, after engagement with its ligands PD-L1 and PD-L2, serves as a key mediator of peripheral tolerance. However, PD-1 signaling also has detrimental effects on T cell function by posing breaks on antitumor and antiviral immunity. PD-1 blocking immunotherapy either alone or in combination with other therapeutic modalities has shown great promise in cancer treatment. However, it is unclear why only a small fraction of patients responds to this type of therapy. For this reason, efforts to better understand the mechanisms of PD-1 function have recently been intensified, with the goal to reveal new strategies to overcome current limitations. The signaling pathways that are inhibited by PD-1 impact key regulators of metabolism. Here, we provide an overview of the current knowledge about the effects of PD-1 on metabolic reprogramming of immune cells and their consequences on systemic metabolism.

Keywords: PD-1; T cell exhaustion; T cells; adaptive and innate immunity; immunometabolism; metabolic reprogramming

DOI: https://doi.org/10.20900/immunometab20220007

J Dermatolog Treat. 2022 Apr 08. 1-12

The dark side of the moon: the immune-mediated adverse events of IL-17A/IL-17R inhibition.

Francesco Messina, Stefano Piaserico.

As aberrant IL-17 signaling plays a critical role in the pathogenesis of psoriasis, biologic agents targeting this pathway have become an important weapon against this disease. Some biologic agents such as IL-17 inhibitors (secukinumab and ixekizumab) and the IL-17 receptor (IL17R) inhibitor (brodalumab) are relatively safe, tolerable and efficacious drugs. Nevertheless, side effects of IL-17 pathway inhibition occur. This review focuses on the dermatological manifestations linked to these treatments. Paradoxical psoriasis and atopic-like eczema may be the most common cutaneous adverse events, while manifestations such as neutrophilic dermatoses, hypersensitivity reactions, lichenoid eruptions, vasculitides, bullous diseases, lupus-like reactions, pigmentation disorders, adnexal diseases and granulomatous dermatoses have been described less frequently.

Keywords: Biologic therapy; IL-17; brodalumab; ixekizumab; secukinumab

DOI: https://doi.org/10.1080/09546634.2022.2062281

Crit Rev Immunol. 2021 ;41(4): 55-88

Natural Killer T Lymphocytes Integrate Innate Sensory Information and Relay Context to Effector Immune Responses.

Sebastian Joyce, Gosife Donald Okoye, Luc Van Kaer.

It is now appreciated that a group of lymphoid lineage cells, collectively called innate-like effector lymphocytes, have evolved to integrate information relayed by the innate sensory immune system about the state of the local tissue environment and to pass on this context to downstream effector innate and adaptive immune responses. Thereby, innate functions engrained into such innate-like lymphoid lineage cells during development can control the quality and magnitude of an immune response to a tissue-altering pathogen and facilitate the formation of memory engrams within the immune system. These goals are accomplished by the innate lymphoid cells that lack antigen-specific receptors, γδ T cell receptor (TCR)-expressing T cells, and several αβ TCR-expressing T cell subsets-such as natural killer T cells, mucosal-associated invariant T cells, et cetera. Whilst we briefly consider the commonalities in the origins and functions of these diverse lymphoid subsets to provide context, the primary topic of this review is to discuss how the semi-invariant natural killer T cells got this way in evolution through lineage commitment and onward ontogeny. What emerges from this discourse is the question: Has a "limbic immune system" emerged (screaming quietly in plain sight!) out of what has been dubbed "in-betweeners"?

DOI: https://doi.org/10.1615/CritRevImmunol.2021040076