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  • The spatial effects of Ebi involve the creation

    2022-06-23

    The spatial effects of Ebi2 involve the creation of a moderate bias in CD4+ T cell distribution toward the LN periphery. Is this modest effect meaningful in an evolutionary sense? In this regard, we think the following considerations are relevant. First, asymmetric CD4+ T cell positioning is highly conserved among multiple inbred mouse strains and anatomical locations as well as in human tissues (unpublished observations) and remains in the absence of microbial signals. Second, infection-related changes in irak pathway have notable effects on gene transmission and hence operate to select the hosts with more effective immunity. Malaria is well recognized for its ability to apply potent selection pressure (Kwiatkowski, 2005). Therefore, the dramatic loss we report here for protection against blood-stage malaria in conditions in which Ebi2-driven CD4+ T cell positioning is absent stands as a powerful argument for the biological importance of the spatial organization we report. Relating structure and function in in vivo settings is central to understanding normal physiology and its disruption in pathological states. The insights provided here into how adaptive T cell immunity is supported by pre-localization of key interacting cell populations emphasizes the role of fine-grained tissue organization in building robustness and efficiency into a system requiring the timely interaction of rare cells. Our observations have relevance for the design of humoral and/or cell-mediated vaccines that depend on optimal CD4+ T cell activity, while pointing to previously unrecognized aspects of lymphoid tissue organization that if disrupted by infection or genetic abnormality may have profound consequences for host defense.
    STAR★Methods
    Acknowledgments We thank V. Durai, T.L. Murphy, and K.M. Murphy for providing Flt3L−/− and Irf4−/− animals; N. Sakaguchi for providing Rag1-GFP mice; J. Furze, A. Worth, A. Turner, and the Jenner Institute Viral Vector Core facility for providing the Ad5.OVA vaccine construct; and A.M. Salman, S.M. Khan, and C.J. Janse for providing the transgenic chimeric P. Berghei-OVA sporozoite line. We acknowledge T.L. Murphy, K.M. Murphy, H. Wong, and A. Radtke for critical manuscript review. We thank all members of the Lymphocyte Biology Section for helpful comments during the course of these studies. This work was supported by the Intramural Research Programs of NIAID and the Clinical Center, NIH. Additionally, Y.H. was supported by NIAID K99 award 1K99AI123350-01A1, and V.S.S. was supported by NIH grant RO1 AI083279.
    Introduction Therapy of autoimmune diseases with T regulatory cells (Treg) is being exceedingly explored. The role of these Treg is to inhibit autoreactive cells and regain self-tolerance. There is a number of Treg populations that control inflammatory processes and counter-act the development of autoimmune reaction, however, one population (CD4+CD25highCD127−) characterized by the expression of FoxP3 is usually used for the cell therapy (Liu et al., 2006; reviewed in Milward et al., 2017 and Stojanovic et al., 2017). Recent clinical trials (phase I) indicate that treatment of newly-diagnosed diabetic children and adults with in vitro expanded polyclonal Treg (cells specific for various antigens) is safe, with no adverse effects and in two cases provided insulin-free period up to 2 years (Marek-Trzonkowska et al., 2012; Marek-Trzonkowska et al., 2014; Bluestone et al., 2015). In contrast to commonly used polyclonal Treg, antigen-specific Treg provide a number of advantages: lower number of cells needed for the effective therapy, avoidance of general immunosuppression, specific Treg traffic to tissues under inflammation. The usage of antigen-specific Treg is mainly restricted to the transgenic animal models of T1D due to their very low numbers in vivo. It was shown that the presence of the antigen is mandatory for the prevention of T1D in NOD mice by Treg (Tonkin et al., 2008). If Treg are polyclonal, i.e. they recognize a variety of different antigens, they are less efficient in diabetes prevention in animal models compared to autoantigen-specific Tregs (either used in the BDC2.5 transgenic T1D mouse model or in NOD mice) (Tarbell et al., 2004; Masteller et al., 2005; Tang et al., 2004). Also, greater number of polyclonal Treg is needed for achieving the same effect as with antigen-specific cells. Moreover, this infusion of large numbers of polyclonal Treg significantly increases the potential risk of non-specific immune suppression, such as the transient increase in viral reactivation in patients receiving cord blood-derived Treg (Tang and Lee, 2012). As for the quantity of autoantigen-specific Treg, in some cases, as little as 5000 Treg were sufficient to prevent T1D (Tarbell et al., 2004). It is reasonable to assume that the efficacy of these autoantigen-specific Tregs ensues from their direct and specific inhibitory action on autoantigen-specific pathogenic T cells.