Sex impacts Th1 cells, Tregs, and DCs in both intestinal and systemic immunity in a mouse strain and location-dependent manner

Background: Males and females have a different predisposition for the development of intestinal disorders, like inflammatory bowel disease (IBD). We hypothesized that sex specific differences in intestinal immune responses may underlie this bias. To test this hypothesis, we studied sex differences in immune cell populations in the Peyer's patches (PP). For comparison with systemic immunity, we studied spleen cells. Methods: Two mouse strains with different susceptibility for developing colitis (BALB/c and C57Bl/6) were used. Using flow cytometry, we measured the percentage of T cells, Th1, Th17, and Treg cells in the PP and spleen. In addition, we measured the percentages of NK cells, macrophages, myeloid, and lymphoid dendritic cells (DCs) and their expression of CD80 and CD103. Moreover, we measured percentages of monocyte subsets in the peripheral circulation. Results were tested using two-way ANOVA, p <0.05. Results: Males had a lower percentage of T cells in both PP and spleen (PP BALB/c 22.1 %, B6 13.6 %; spleen BALB/c 4.7 %, B6 19.9 %) but a higher percentage of Th1 cell in both tissues (PP BALB/c 350 %, B6 109.5 %; spleen BALB/c 48.7 %, B6 41.9 %) than females. They also had a higher percentage of Tregs in the spleen than females (BALB/c 20.5 %, B6 4.5 %). Furthermore, males had a higher percentage of CD80(+) DCs in both the PP and spleen (lymphoid DCs in PP BALB/c 104.7 %, B6 29.6 %; spleen BALB/c 72.2 %, B6 44.2 %; myeloid DCs in PP BALB/c 80.5 %, B6 93.3 %; spleen BALB/c 88.5 %, B6 50.8 %) and a higher percentage of lymphoid CD103(+) DCs in the spleen than females (BALB/c 41.5 %, B6 28.3 %). The percentage of NK cells was decreased in the spleen (BALB/c 12.5 %, B6 25.1 %) but increased in the PP (BALB/c 75.7 %, B6 78.6 %) of males as compared with females. Strain differences were also found in the PP; BALB/c mice had a higher percentage of T cells (males 58.1 %, females 75.5 %), a higher Th/Tc ratio (males 81.0 %, females 134.2 %), less FoxP3(+)CD25(-) T cells (males 14.6 %, females 30.0 %), more DCs (males 14.8 %, females 15.7 %) and macrophages (males 67.9 %, females 141.2 %), and more NK cells (males 160 %, females 164.3 %) than BALB/c mice. Conclusions: In this study, we show sex differences in intestinal and peripheral immune populations. These differences may underlie sex differences in intestinal disorders like IBD, and this information may be an important knowledge for the treatment of intestinal-related diseases

MAIT cells are imprinted by the microbiota in early life and promote tissue repair

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury

TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs

Tissue-specific differentiation of colonic macrophages requires TGFβ receptor-mediated signaling

Intestinal macrophages (mφ) form one of the largest populations of mφ in the body and are vital for the maintenance of gut homeostasis. They have several unique properties and are derived from local differentiation of classical Ly6Chi monocytes, but the factors driving this tissue-specific process are not understood. Here we have used global transcriptomic analysis to identify a unique homeostatic signature of mature colonic mφ that is acquired as they differentiate in the mucosa. By comparing the analogous monocyte differentiation process found in the dermis, we identify TGFβ as an indispensable part of monocyte differentiation in the intestine and show that it enables mφ to adapt precisely to the requirements of their environment. Importantly, TGFβR signaling on mφ has a crucial role in regulating the accumulation of monocytes in the mucosa, via mechanisms that are distinct from those used by IL10

Barrier Tissue Macrophages: Functional Adaptation to Environmental Challenges

Macrophages are found throughout the body, where they have crucial roles in tissue development, homeostasis and remodeling, as well as being sentinels of the innate immune system that can contribute to protective immunity and inflammation. Barrier tissues, such as the intestine, lung, skin and liver, are exposed constantly to the outside world, which places special demands on resident cell populations such as macrophages. Here we review the mounting evidence that although macrophages in different barrier tissues may be derived from distinct progenitors, their highly specific properties are shaped by the local environment, which allows them to adapt precisely to the needs of their anatomical niche. We discuss the properties of macrophages in steady-state barrier tissues, outline the factors that shape their differentiation and behavior and describe how macrophages change during protective immunity and inflammation

Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities

Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80(hi)GATA6(+) macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C(+) monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80(lo)MHCII(+) cells that act, in part, as precursors of F4/80(hi)GATA6(+) macrophages. Notably, monocyte-derived F4/80(hi) macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age

Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice

The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2–dependent influx of Ly6Chi monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool