Intestinal CD8αα IELs derived from two distinct thymic precursors have staggered ontogeny

Abstract

CD8αα intraepithelial lymphocytes (IELs) are abundant T cells that protect the gut epithelium. Their thymic precursors (IELps) include PD-1+ type A and Tbet+ type B populations, which differ in their antigen-receptor specificities. To better understand CD8αα IEL ontogeny, we performed “time-stamp” fate mapping experiments and observed that it seeds the intestine predominantly during a narrow time window in early life. Adoptively transferred IELps parked better in the intestines of young mice than in adults. In young mice, both type A and type B IELps had an S1PR1+ and α4β7+ emigration- and mucosal-homing competent phenotype, while this was restricted to type A IELps in adults. Only CD8αα IELs established in early life were enriched in cells bearing type B IELp TCR usage. Together, our results suggest that the young intestine facilitates CD8αα IEL establishment and that early IELs are distinct from IELs established after this initial wave. These data provide novel insight into the ontogeny of CD8αα IELs.

Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells

“…Because murine IELps were shown to downregulate PD-1 expression during differentiation and PD-1 - (T-bet + ) IELp populations were described 26,27 , the unconventional CD3 +/low PD-1 + CB population may not include the complete human uIEL population, but only the more recent thymic emigrants of that population. Therefore, the discriminatory markers identified above were used in a flow cytometric analysis of the entire CD3 +/low TCRγδ - CD4 - CD8α + fraction in CB (fig.…”

Dietary environmental factors shape the immune defence againstCryptosporidiuminfection

“…CD8 + IELs (natural CD8aa and induced CD8αβ) in the gut are long-lived tissue-resident memory cells. Natural CD8aa cells populate the relatively abiotic guts of pups in response to self-antigens during weaning (Ruscher et al, 2020), while CD8αβ IELs accumulate over time in response to externallyderived antigens (Cheroutre et al, 2011). While the exact mechanism by which these IELs sense epithelial injury during infection is unclear (Hoytema van , being in a constant state of heightened activation with increased cytolytic granzyme expression (Konjar et al, 2018) increases their ability to swiftly act on Cryptosporidiuminfected epithelial cells.…”

Innate and Innate-like Effector Lymphocytes in Health and Disease

“…In addition to innate IELs and natural gd IELs discussed above, the intestinal epithelium contains ab IELs with innate-like characteristics and functions (9,125). These natural ab IELs express CD8aa in the absence of CD8ab or CD4 and are derived from thymic precursors that upon leaving the thymus during a narrow time window in early life rapidly seed the epithelium and induce CD8aa expression in response to TGF-b signaling (9,125,126). The specificity of these cells is uncertain but likely involves both classical and nonclassical MHC products.…”