Memory/effector T cells traffic efficiently through extralymphoid tissues, entering from the blood and leaving via the afferent lymph. During inflammation, T cell traffic into the affected tissue dramatically increases; however, the dynamics and mechanisms of T cell exit from inflamed tissues are poorly characterized. Here we show, using both a mouse and a sheep model, that large numbers of lymphocytes leave the chronically inflamed skin. Many T cells capable of producing IFN-γ and IL-17 also entered the draining afferent lymph, demonstrating that memory/effector T cells egress from sites of inflammation. Whereas efficient egress from acutely inflamed skin required lymphocyte-expressed CCR7, chronic inflammation promoted significant CCR7-independent exit as well. Lymphocyte exit at late time points of inflammation was sensitive to pertussis toxin but only partially affected by the drug FTY720, implying the contribution of alternative chemoattractant receptors other than S1P1. Our data show that CCR7 is an important receptor for lymphocyte egress from both resting and inflamed extralymphoid tissues, but that alternative exit receptors come into play during chronic inflammation.
B cells infiltrate the skin in many chronic inflammatory diseases caused by autoimmunity or infection. Despite potential contribution to disease, skin-associated B cells remain poorly characterized. Using an ovine model of granulomatous skin inflammation, we demonstrate that B cells increase in the skin and skin-draining afferent lymph during inflammation. Surprisingly, skin B cells are a heterogeneous population that is distinct from lymph node B cells, with more large lymphocytes as well as B-1-like B cells that co-express high levels IgM and CD11b. Skin B cells have increased MHCII, CD1, and CD80/86 expression compared with lymph node B cells, suggesting that they are well-suited for T cell activation at the site of inflammation. Furthermore, we show that skin accumulation of B cells and antibody-secreting cells during inflammation increases local antibody titers, which could augment host defense and autoimmunity. While skin B cells express typical skin homing receptors such as E-selectin ligand and alpha-4 and beta-1 integrins, they are unresponsive to ligands for chemokine receptors associated with T cell homing into skin. Instead, skin B cells migrate toward the cutaneously expressed CCR6 ligand CCL20. Our data support a model in which B cells use CCR6-CCL20 to recirculate through the skin, fulfilling a novel role in skin immunity and inflammation.
Memory/effector T cells traffic efficiently through extralymphoid tissues entering from the blood and leaving via the afferent lymph. During inflammation, T cell traffic through the affected tissue dramatically increases, however, dynamics and mechanisms of T cell exit from inflamed tissues are poorly characterized. Here we show that, unexpectedly, large numbers of lymphocytes including T cells capable of producing IFN-γ and IL-17 leave the chronically inflamed skin, showing that memory/effector T cells also egress sites of inflammation. Whereas efficient egress from acutely inflamed skin required lymphocyte-expressed CCR7, chronic inflammation promoted CCR7-independent exit. CCR7-independent exit at late time points of inflammation was sensitive to pertussis toxin implying the contribution of alternative chemoattractant receptors. Our data suggest that CCR7 is an important receptor for lymphocyte egress from both resting and inflamed tissues, but that alternative exit receptors come into play during chronic inflammation allowing the egress of CCR7- as well as CCR7+ lymphocytes.
B cells infiltrate skin in many chronic inflammatory diseases caused by autoimmunity or infection. Despite their potential to contribute to disease processes, skin-associated B cells remain poorly characterized. Here, we find in an ovine granuloma model of cutaneous inflammation, B cells increase during the chronic phase of inflammation in both relative and absolute number in the skin and skin-draining afferent lymph. Surprisingly, these B cells are a heterogeneous population that is phenotypically distinct from the B cell population in lymph nodes with more ‘innate-like’ B cells co-expressing high levels IgM and CD11b. Furthermore, skin B cells have increased MHCII and CD80/86 expression compared to lymph node B cells, suggesting that they are well-suited for T cell activation at the site of inflammation. Additionally, unlike co-isolated T cells, skin B cells are not responsive to ligands of chemokine receptors typically associated with skin homing, implying that they utilize alternative chemokine receptors to migrate to the skin. In summary, our data show that a population of B cells recirculates through uninflamed and inflamed skin, fulfilling a so far unappreciated role in skin immunity.
B cells infiltrate extralymphoid tissues in many chronic inflammatory diseases, including cutaneous manifestations of autoimmunity as well as infection. However, the phenotype and function of B cells in the skin remains poorly understood. In a granuloma model of cutaneous inflammation in sheep and mice, B cells increase during the chronic phase of inflammation in both percentage and absolute number in the skin and skin-draining afferent lymph. B cells in the skin and skin-draining lymph are a heterogeneous population that is phenotypically distinct from B cell populations in the spleen and lymph nodes. Many skin B cells exhibit an ‘innate-like’ phenotype co-expressing IgM and CD11b. Furthermore, skin B cells have increased MHCII and CD80/86 expression compared to lymph node or splenic B cells, suggesting that they are well-suited for T cell activation at the site of inflammation. Additionally, skin B cells are not responsive to ligands of chemokine receptors typically associated with skin homing. The data support a model in which innate-like B cells use alternative chemokine receptors to migrate to the skin where they support inflammatory or protective immune responses.
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