CD4+CD25+ Regulatory T Cell Ontogeny and Preferential Migration to the Cecal Tonsils in Chickens

PLOS ONE, Mar 2012

Thymic CD4+CD25+ cells have regulatory-T-cell-like properties in chickens. This study examined the ontogeny of CD4+CD25+ cells in the thymus and in peripheral compartments in chickens. CD4+CD25+ cells started to appear in the thymus at day 15 of incubation (E15), although at low percentages. Expressed as a percentage of CD4+ cells, CD4+CD25+ cells increased (P<0.01) from 1.7% at E20 to 7.3% at 0 d post-hatch (D0). CD4+CD25+ cells did not appear in the spleen or cecal tonsils of embryos. Expressed as a percentage of CD4+ cells, CD4+CD25+ cells increased (P<0.01) from 0% at D0 to 27% at D1 in cecal tonsils and from 0% at D0 to 11% at D1 in the spleen. Expressed as a percentage of all mononuclear cells, cecal tonsils at D1 had approximately 3.5-fold higher percentage of CD4+CD25+ cells than the spleen at D1. CD4+CD25+ cells from cecal tonsils of chicks at D1 were suppressive. CD4+CD25+ cells from D0 thymus, when injected back into MHC-compatible chicks, migrated to cecal tonsils and lungs and were detected until 10 d post-injection. CD4+CD25+ cells from cecal tonsils had a higher (P = 0.01) relative amount of CCR9 mRNA than CD4+CD25+ cells from the thymus. It could be concluded that in chickens CD4+CD25+ cells migrate from the thymus immediately post-hatch and preferentially colonize the gut associated lymphoid tissues. CD4+CD25+ cells' preferential migration to cecal tonsils is likely directed through the CCR9 pathway in chickens.

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CD4+CD25+ Regulatory T Cell Ontogeny and Preferential Migration to the Cecal Tonsils in Chickens

Selvaraj RK (2012) CD4+CD25+ Regulatory T Cell Ontogeny and Preferential Migration to the Cecal Tonsils in Chickens. PLoS ONE 7(3): e33970. doi:10.1371/journal.pone.0033970 + + CD4 CD25 Regulatory T Cell Ontogeny and Preferential Migration to the Cecal Tonsils in Chickens Revathi Shanmugasundaram 0 Ramesh K. Selvaraj 0 Oliver Frey, University Hospital Jena, Germany 0 Department of Animal Sciences, Ohio Agricultural Research and Development Center , Wooster, Ohio , United States of America Thymic CD4+CD25+ cells have regulatory-T-cell-like properties in chickens. This study examined the ontogeny of CD4+CD25+ cells in the thymus and in peripheral compartments in chickens. CD4+CD25+ cells started to appear in the thymus at day 15 of incubation (E15), although at low percentages. Expressed as a percentage of CD4+ cells, CD4+CD25+ cells increased (P,0.01) from 1.7% at E20 to 7.3% at 0 d post-hatch (D0). CD4+CD25+ cells did not appear in the spleen or cecal tonsils of embryos. Expressed as a percentage of CD4+ cells, CD4+CD25+ cells increased (P,0.01) from 0% at D0 to 27% at D1 in cecal tonsils and from 0% at D0 to 11% at D1 in the spleen. Expressed as a percentage of all mononuclear cells, cecal tonsils at D1 had approximately 3.5-fold higher percentage of CD4+CD25+ cells than the spleen at D1. CD4+CD25+ cells from cecal tonsils of chicks at D1 were suppressive. CD4+CD25+ cells from D0 thymus, when injected back into MHC-compatible chicks, migrated to cecal tonsils and lungs and were detected until 10 d post-injection. CD4+CD25+ cells from cecal tonsils had a higher (P = 0.01) relative amount of CCR9 mRNA than CD4+CD25+ cells from the thymus. It could be concluded that in chickens CD4+CD25+ cells migrate from the thymus immediately post-hatch and preferentially colonize the gut associated lymphoid tissues. CD4+CD25+ cells' preferential migration to cecal tonsils is likely directed through the CCR9 pathway in chickens. - Funding: This research was supported by an OARDC (Ohio Agricultural Research and Development Center) SEEDS grant and George and Edna Jaap funding awarded to RKS. Salaries and research support were provided by state and federal funds appropriated to The Ohio State University, Ohio Agricultural Research and Development Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Regulatory T cells (Tregs) are a subset of T cells involved in immune suppression. In mammals, Tregs are initially defined by the expression of CD4 and CD25 [1], though FoxP3 was later identified as a master regulator [2] and a specific marker for Tregs [3]. We previously described thymic CD4+CD25+ cells to have Treg-like properties in chickens, even though chickens lack FoxP3 [4]. In chickens, thymic CD4+CD25+ cells have the classical properties of Tregs, like high IL-10, TGF-b, cytotoxic Tlymphocyte antigen 4, and lymphocyte-activation gene 3 mRNA amounts, and they suppress nave T cell proliferation in vitro [4]. In chickens, CD4+CD25+ cells are present in high numbers in mucosal regions like cecal tonsils and lungs. CD25, though is widely used as Treg marker, is not a Treg-specific marker and in periphery activated T cells can express CD25 transiently [5]. In mammals, Tregs develop in the thymus [6]. Initial export of Tregs from the thymus was originally proposed to occur between day 2 and 4, by which time conventional T cells have already migrated to the periphery [7]. This hypothesis is based on the observation that surgical neonatal thymectomy of normal mice, between day 2 and 4 after birth, led to autoimmune diseases [8] and that transferring Tregs prevents the induction of autoimmune diseases in d 3 thymectomized mice [1]. However, other studies have shown the presence of Tregs in the periphery of three-dayold mice [9] and, hence, it was later proposed that Tregs are exported from the thymus, along with conventional T cells, before birth [10]. In chicken embryos, the thymus is colonized in three distinct waves at 6.5, 12, and 18 days of incubation, and each wave is followed by export of lymphocytes [11,12]. Export of lymphocytes from the thymus to colonize peripheral lymphoid organs also occurs in discrete waves [13]. The ontogeny of CD4+CD25+ cells in both the thymus and peripheral compartments in chickens has not been studied. In chickens [4] as well as in mammals [14], CD4+CD25+ Tregs preferentially migrate to the mucosal-associated lymphoid tissues. In mice, Treg migration to the mucosal-associated lymphoid tissue of the gut is directed through the chemokine receptor type 9 (CCR9) pathway [15]. The objectives of this study are to analyze the percentage of CD4+CD25+ cells in the thymic lobes, spleens, and cecal tonsils of developing embryos and of chicks post-hatch. In addition, the migration pattern of thymic CD4+CD25+ cells were studied. Thymic CD4+ (...truncated)


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Revathi Shanmugasundaram, Ramesh K. Selvaraj. CD4+CD25+ Regulatory T Cell Ontogeny and Preferential Migration to the Cecal Tonsils in Chickens, PLOS ONE, 2012, Volume 7, Issue 3, DOI: 10.1371/journal.pone.0033970