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  • One clue to how evolution has solved such

    2021-11-22

    One clue to how evolution has solved such spatiotemporal challenges comes from studies revealing that lymph node (LN) organization is more complex than originally presumed, suggesting that steady-state microanatomical features are crucial for effective immune responses (reviewed by Qi et al., 2014). For instance, positioning of various innate and innate-like lymphocytes close to subcapsular macrophages drives rapid responses that prevent the systemic spread of pathogens (Fang et al., 2017, Kastenmüller et al., 2012); localized delivery of interleukin-4 (IL-4) at the interfollicular region by natural killer T (NKT) Cyclophosphamide mg promotes the generation of class-switched antibody-secreting cells (Gaya et al., 2018). Given these findings, an important question is whether there is an unrecognized level of LN organization that contributes to effective adaptive T cell responses. T lymphocytes are predominantly confined to the paracortical region (T cell zone) of the LN, where they migrate along a network of DC-studded fibroblastic reticular cells in search of cognate antigen (Bajénoff et al., 2006, Sixt et al., 2005). This region is thought to harbor a mixture of CD4+ and CD8+ T cells that follow a random walk migration pattern (Girard et al., 2012, Krummel et al., 2016) until cognate interactions occur and drive chemokine-directed clustering of relevant cell populations (Brewitz et al., 2017, Castellino et al., 2006). However, recent data have revealed a finer-grained spatial organization of the cellular components involved in T cell adaptive immunity than previously recognized. In particular, cDC1s with a preferential capacity for antigen cross-presentation via major histocompatibility complex class I (MHC class I) molecules to CD8+ T cells (den Haan et al., 2000, Schnorrer et al., 2006) are concentrated in the central paracortical T cell zone, whereas cDC2s with a bias for presentation to CD4+ T cells via MHC class II molecules (Dudziak et al., 2007, Vander Lugt et al., 2014) are enriched in the subcapsular sinus floor and adjacent regions of the paracortex and interfollicular areas (Gerner et al., 2012). A similar peripheral versus central distribution of these two DC subsets has been previously reported for the spleen (Calabro et al., 2016, Dudziak et al., 2007). Considering both the requirement for timely and effective responses centered around specialized LN environments and these data showing differential positioning of DC subsets within secondary lymphoid structures, we hypothesized that there might also exist an unrecognized corresponding spatial pre-organization of T cell subsets that optimizes immune responses by effectively shrinking the volume in which the T cell search for ligand is conducted. In agreement with this hypothesis, we show that the spatially distinct localization of cDC2 (Gerner et al., 2012) is matched by a similar peripheral bias in steady-state paracortical naive CD4+ T cell distribution that is dependent on expression of the oxysterol receptor Ebi2 by these lymphocytes. This match in intranodal spatial distribution results in the formation of an anatomical platform for enhanced antigen presentation and recognition in the context of MHC class II molecules. In the absence of this peripherally biased distribution, CD4+ T cells were delayed in antigen recognition, expansion, differentiation, and provision of helper function to CD8+ T cells, preventing proper control of helminth infection by T helper-2 (Th2) CD4+ T cell effectors and protection against liver stage malaria infection mediated by vaccine-induced, help-dependent CD8+ memory T cell responses. These findings suggest that evolution has operated to enforce an ordered topography on crucial interacting immune components in LNs to optimize effective adaptive T cell responses to pathogens.
    Results
    Discussion The adaptive immune system faces a substantial challenge: it must provide rapid and robust immunity for the host without a priori knowledge of when and where a given pathogen will invade. This challenge is compounded by the fact that the frequency of antigen-specific lymphocytes is extremely low, as well as the fact that these rare cells are not stationary but continuously recirculate. The findings presented here provide strong evidence that overcoming these limitations and producing optimal immune responses is intimately linked to the microanatomy of lymphoid tissues. Our studies revealed a previous overlooked aspect of naive T cell localization within secondary lymphoid tissues: naive CD4+ T cell enrichment at the periphery of the LN paracortex in close proximity to antigen delivered via afferent lymphatics and a high density of cDC2 DCs optimally suited to their antigen-specific activation. Mechanistically, this enrichment depended on CD4+ T cell sensing of oxysterols via the GPCR Ebi2. Functionally, such positioning promoted a timely and maximal CD4+ T cell response in two ways: (1) by reducing the search space that must be traversed to locate suitable antigen-bearing DCs and (2) by increasing the probability of naive CD4+ T cells being recruited to an activated state by facilitating engagement with the peripheral cDC2s that acquire the highest amount of antigen draining into the LN. Acting at the very early stages of the immune response, this mechanism ensured efficient initiation of CD4+ effector and helper T cell responses, with a profound impact on effective control of pathogens.