Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8⁺ T cells

Abstract

Survival of antigen-specific CD8+ T cells in peripheral lymphoid organs during viral infection is known to be dependent predominantly on IL-7 and IL-15. However, little is known about a possible influence of tissue environmental factors on this process. To address this question we studied survival of memory antigen-specific CD8+ T cells in the small intestine. Here, we show that 2 months after vaccinia virus infection, B8R20–27/H2-Kb tetramer+ CD8+ T cells in the small intestinal intraepithelial (SI-IEL) layer are found in mice deficient in IL-15 expression. Moreover, SI-IEL and lamina propria lymphocytes do not express the receptor for IL-7 (IL-7Rα/CD127). In addition, after in vitro stimulation with B8R20–27 peptide, SI-IEL cells do not produce high amounts of IFN-γ either at 5 days (5d) or at 2 months post infection (p.i.). Importantly, the lack of IL-15 was found to shape the functional activity of antigen-specific CD8+ T cells, by narrowing the CTL avidity repertoire. Taken together, these results reveal that survival factors as well as functional activity of antigen-specific CD8+ T cells in the SI-IEL compartments may markedly differ from their counterparts in peripheral lymphoid tissues.

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

“…Enhancers neighboring several genes in GO categories involved in leukocyte and lymphocyte activation and cytokine interactions also exhibited significant increases in accessibility with colonization in TCR γδ + IELs (Dataset S10D); these genes include Cd28, Cxcr4, Il15ra, Il2, Il10, Cd40lg, and Ccr7, some of which are associated with the activation of T cells and have been implicated in shaping the IEL compartment. As noted above, IL-15 responsiveness has been shown to be key for the accumulation of CD8αα + TCRβ + cells and also for TCR γδ + cells (25)(26)(27)(28).…”

“…These include ahr, encoding the aryl hydrocarbon receptor (AhR), which controls accumulation of CD8αα + TCRβ + IELs (23); id2, which is required for accumulation of CD8αβ + IELs (24); il15ra (IL15 receptor α), which encodes a component of the IL-15 receptor; and il7r, which specifies a component of the IL-7 receptor. IL-15 and IL-7 are important cytokines controlling the accumulation and function of CD8αα + IELs (25)(26)(27)(28). Additionally, members of two pathways, KEGG "Cell adhesion molecules" (35 genes) and KEGG "ECM-receptor interaction" (25 genes), were also associated with enhancers exhibiting increased accessibility in CONV-R compared to GF TCR αβ + IELs (Dataset S10A); changes in chromatin state affecting enhancers positioned next to genes in these pathways may reflect broad changes in TCR αβ + interactions with the intestinal epithelium upon colonization.…”

Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine

“…We also demonstrate that we can isolate distinct populations of monocytes, macrophages, neutrophils and dendritic cells from the small intestine LP of helminth-infected animals, which had previously been a particular challenge due to the fragile nature of myeloid cells ex-vivo. Together, our data indicate that the isolation protocol that we present here allows the phenotypic and functional The isolation of viable leukocytes from the intestinal LP of naïve mice or those infected with bacterial, viral and protozoan pathogens has been widely published (Bravo-Blas et al, 2019;Cerovic et al, 2013;Goodyear et al, 2014;Isakov et al, 2011;Perona-Wright et al, 2012). In contrast, helminth-infected tissues have been difficult to use as sources of immune cells.…”

TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes

“…This may be because the expression of IL-15 in intestinal mucosa was reduced but not completely lost in TLR2 −/− mice, which is consistent with our immunohistochemistry findings ( Figure 4(b) ). Alternatively, the IELs may depend for their development and maintenance on factors other than IL-15, such as IL-2 and IL-7 [ 24 , 25 ].…”