Su1880 RORγt-Dependent CD4+ T Cells Garden the Mucosa-Associated Microbiome of the Small Intestine and Colon

ABSTRACTGut resident regulatory CD4+ T (Tregs) cells in mice are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and the gut microbiota. In contrast, information about the phenotype and function of Tregs in the human gut is limited. Here, we performed a detailed characterization of Foxp3+ CD4 Tregs in human small intestine (SI). SI Foxp3+ CD4 T cells were CD45RA-CTLA4+CD127- and suppressed proliferation of autologous T cells. Approximately 60% of SI Tregs expressed the transcription factor Helios. When stimulated, Helios- Tregs produced IL-17, IFNγ and IL-10, whereas Helios+ Tregs produced very low levels of these cytokines. Sampling mucosal tissue from transplanted human duodenum we demonstrated that donor SI Helios+ Tregs have a rapid turnover rate whereas Helios- Tregs persisted for at least 1 yr post transplantation. In the normal SI, Foxp3+ Tregs constituted only 2% of all CD4 T cells, while in active celiac disease both subsets expanded 5-10-fold. Taken together, these findings suggest that human SI contains two phenotypically and functionally distinct Treg subsets (Helios+ and Helios- Tregs), which are reminiscent of rapidly renewed dietary antigen-specific Tregs and microbiota-specific Tregs resident in the mouse gut, respectively.

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HLA restriction patterns of gliadin- and astrovirus-specific CD4+ T cells isolated in parallel from the small intestine of celiac disease patients

Tissue Antigens ◽

10.1111/j.1399-0039.1998.tb03066.x ◽

1998 ◽

Vol 52 (5) ◽

pp. 407-415 ◽

Cited By ~ 17

Author(s):

Ø. Molberg ◽

K.E.A. Lundin ◽

E.M. Nilsen ◽

H. Scon ◽

K. Kett ◽

...

Keyword(s):

T Cells ◽

Small Intestine ◽

Celiac Disease ◽

Cd4 T Cells ◽

Restriction Patterns ◽

Hla Restriction

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Origin, trafficking, and intraepithelial fate of gut-tropic T cells

Journal of Experimental Medicine ◽

10.1084/jem.20122588 ◽

2013 ◽

Vol 210 (9) ◽

pp. 1839-1854 ◽

Cited By ~ 48

Author(s):

Delphine Guy-Grand ◽

Pierre Vassalli ◽

Gerard Eberl ◽

Pablo Pereira ◽

Odile Burlen-Defranoux ◽

...

Keyword(s):

T Cells ◽

Small Intestine ◽

Steady State ◽

Cd4 T Cells ◽

Lymphoid Tissue ◽

Granzyme B ◽

Intraepithelial Lymphocytes ◽

Recent Thymic Emigrants ◽

Developmentally Regulated

The small intestine epithelium (SI-Ep) harbors millions of unconventional (γδ and CD4− CD8− NK1.1− TCRαβ) and conventional (CD8αβ and CD4) T cells, designated intraepithelial lymphocytes (IELs). Here, we identified the circulating pool of SI-Ep–tropic T cells and studied their capacity to colonize the SI-Ep under steady-state conditions in SPF mice. Developmentally regulated levels of α4β7 endowed recent thymic emigrants (RTEs) of unconventional types with higher SI-Ep tropism than their conventional homologues. SI-Ep–tropic RTEs, which in all lineages emerged naive, homed to the SI-Ep, but this environment was inadequate to stimulate them to cycle. In contrast, conventional and, unexpectedly, unconventional T cells, particularly Vγ7+ (hallmark of γδ IELs), previously stimulated to cycle in the gut-associated lymphoid tissue (GALT), proliferated in the SI-Ep. Cycling unconventional SI-Ep immigrants divided far more efficiently than their conventional homologues, thereby becoming predominant. This difference impacted on acquisition of high Granzyme B content, which required extensive proliferation. In conclusion, SI-Ep–tropic T cells follow a thymus–SI-Ep or a GALT–SI-Ep pathway, the latter generating highly competitive immigrants that are the sole precursors of cytotoxic IELs. These events occur continuously as part of the normal IEL dynamics.

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Temporal Dynamics of T Helper Populations in the Proximal Small Intestine after Oral Bovine Lactoferrin Administration in BALB/c Mice

Nutrients ◽

10.3390/nu13082852 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2852

Author(s):

Mario Ynga-Durand ◽

Gabriela Tapia-Pastrana ◽

Xóchitl Abril Rebollar-Ruíz ◽

Mariazell Yépez-Ortega ◽

Oscar Nieto-Yañez ◽

...

Keyword(s):

T Cells ◽

Small Intestine ◽

Transforming Growth Factor Beta ◽

Cd4 T Cells ◽

Transforming Growth Factor ◽

Temporal Dynamics ◽

Saline Control ◽

Bovine Lactoferrin ◽

Intestinal Immunity ◽

Proximal Small Intestine

Bovine lactoferrin (bLf), a component of milk and a dietary supplement, modulates intestinal immunity at effector and inductor sites. Considering the regional difference in intestinal compartments and the dynamics of local cytokine-producing cells in the gut across time, the aim of this work was to characterize the effects of bLf on the proximal small intestine in a BALB/c murine model of oral administration. Male BALB/c mice were treated with oral bLf vs. saline control as mock by buccal deposition for 28 days. Intestinal secretions were obtained at different time points and cells were isolated from Peyer’s patches (PP) and lamina propria (LP) of the proximal small intestine as representative inductor and effector sites, respectively. Total and specific anti-bLF IgA and IgM were determined by enzyme-immuno assay; the percentages of IgA+ and IgM+ plasma cells (PC) and cytokine-producing CD4+ T cells of PP and LP were analyzed by flow cytometry. We found that total and bLf-specific IgA and IgM levels were increased in the intestinal secretions of the bLf group in comparison to mock group and day 0. LP IgA+ PC and IgM+ PC presented an initial elevation on day 7 and day 21, respectively, followed by a decrease on day 28 in comparison to mock. Higher percentages of CD4+ T cells in LP were found in the bLf group. Cytokines-producing CD4+ T cells populations presented a pattern of increases and decreases in the bLf group in both LP and PP. Transforming growth factor beta (TGF-β)+ CD4+ T cells showed higher percentages after bLf administration with a marked peak at day 21 in both LP and PP in comparison to mock-treated mice. Oral bLf exhibits complex immune properties in the proximal small intestine, where temporal monitoring of the inductor and effector compartments reveals patterns of rises and falls of different cell populations. Exceptionally, TGF-β+ CD4+ T cells show consistent higher numbers after bLf intervention across time. Our work suggests that isolated measurements do not show the complete picture of the modulatory effects of oral bLf in immunological sites as dynamic as the proximal small intestine.

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Lactococcus lactis subsp. Cremoris C60 restores T Cell Population in Small Intestinal Lamina Propria in Aged Interleukin-18 Deficient Mice

Nutrients ◽

10.3390/nu12113287 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3287

Author(s):

Suguru Saito ◽

Nanae Kakizaki ◽

Alato Okuno ◽

Toshio Maekawa ◽

Noriko M. Tsuji

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Small Intestine ◽

T Cell ◽

Cd4 T Cells ◽

Interleukin 18 ◽

Intestinal Lamina Propria ◽

Ifn Γ ◽

Small Intestinal ◽

Deficient Mice

Lactic acid bacteria (LAB), a major commensal bacterium in the small intestine, are well known beneficial bacteria which promote establishment of gut-centric immunity, such as anti-inflammation and anti-infection. In this report, we show that a LAB strain Lactococcus lactis subsp. Cremoris C60 possess an ability to activate antigen presenting cells, such as dendritic cells (DCs), and intestinal T cells which possibly support to maintain healthy intestinal immunological environment in aging process. We found that CD4+ T cells in the small intestine are dramatically decreased in aged Interleukin-18 knock out (IL-18KO) mice, associated with the impairment of IFN-γ production in the CD4+ T cells, especially in small intestinal lamina propria (LP). Surprisingly, heat killed-C60 (HK-C60) diet completely recovered the CD4+ T cells population and activity in SI-LP and over activated the population in Peyer’s patches (PPs) of IL-18KO mice. The HK-C60 diet was effective approach not only to restore the number of cells, but also to recover IFN-γ production in the CD4+ T cell population in the small intestine of IL-18-deficient mice. As a possible cause in the age-associated impairment of CD4+ T cells activity in IL-18KO mice, we found that the immunological activity was downregulated in the IL-18-deficient DCs. The cytokines production and cellular activation markers expression were downregulated in the IL-18-deficient bone marrow derived dendritic cells (BMDCs) at the basal level, however, both activities were highly upregulated in HK-C60 stimulation as compared to those of WT cells. Antigen uptake was also attenuated in the IL-18-deficient BMDCs, and it was significantly enhanced in the cells as compared to WT cells in HK-60 stimulation. An in vitro antigen presentation assay showed that IFN-γ production in the CD4+ T cells was significantly enhanced in the culture of IL-18-deficient BMDCs compared with WT cells in the presence of HK-C60. Thus, we conclude that HK-C60 diet possesses an ability to restore T cells impairment in the small intestine of IL-18-deficient environment. In addition, the positive effect is based on the immunological modification of DCs function which directory influences into the promotion of effector CD4+ T cells generation in the small intestine.

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