Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor

Abstract

Peripheral Foxp3 regulatory T cells (pT) maintain immune homeostasis by controlling potentially harmful effector T cell responses toward dietary and microbial antigens. Although the identity of the T cell receptor (TCR) can impose commitment and functional specialization of T cells, less is known about how TCR identity governs pT development from conventional CD4 T cells. To investigate the extent to which TCR identity dictates pT fate, we used somatic cell nuclear transfer to generate a transnuclear (TN) mouse carrying a monoclonal TCR from a pT (pT TN mice). We found that the pT TCR did not inevitably predispose T cells to become pT but instead allowed for differentiation of noninflammatory CD4CD8αα intraepithelial lymphocytes (CD4) in the small intestine. Only when we limited the number of T cell precursors that carried the TN pT TCR did we observe substantial pT development in the mesenteric lymph nodes and small intestine lamina propria of mixed bone marrow chimeras. Small clonal sizes and therefore decreased intraclonal competition were required for pT development. Despite bearing the same TCR, small intestine CD4 developed independently of precursor frequency. Both pT and CD4 development strictly depended on the resident microbiota. A single clonal CD4 T cell precursor can thus give rise to two functionally distinct and anatomically segregated T cell subsets in a microbiota-dependent manner. Therefore, plasticity of the CD4 T cell compartment depends not only on the microbiota but also on specialized environmental cues provided by different tissues.

Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets

“…As is also the case for CD4 + Tregs 46; 52 , in the setting of limited precursor frequency, iNKT cell lineage choice preferences become more apparent. CD1d-presented ligands are not limiting in the thymus, as shown here and by others 38 ; however particular ligands which might instruct development into NKT1, NKT2, or NKT17 lineages, may be less abundant.…”

“…Somatic cell nuclear transfer is a unique tool used to clone mice from antigen-specific lymphocytes 41; 42; 43; 45; 46 including from iNKT cell nuclei 47 . A previous report of transnuclear iNKT cell mice only used mice that express the Vα14 rearranged TCR and relied on polyclonal Vβ expression 47 .…”

Diverse developmental pathways of intestinal intraepithelial lymphocytes

“…Intriguingly, this conversion can be observed among lamina propria regulatory T (T reg ) cells, which subsequently migrate to the intestinal epithelium, lose expression of forkhead box protein P3 (FOXP3) and THPOK and become CD4 + CD8αα + IELs in a microbiota-dependent manner 22 . In further support of this scenario, T cells from mice derived by nuclear transfer from a FOXP3 + T reg cell from the mesenteric lymph node into an enucleated oocyte develop into either lamina propria T reg cells or CD4 + CD8αα + IELs 23 . Thus, CD4 + T cell responses to microbiota antigens may be characterized by plasticity and conversion between the T reg cell and effector IEL programmes 22,23 .…”

“…In further support of this scenario, T cells from mice derived by nuclear transfer from a FOXP3 + T reg cell from the mesenteric lymph node into an enucleated oocyte develop into either lamina propria T reg cells or CD4 + CD8αα + IELs 23 . Thus, CD4 + T cell responses to microbiota antigens may be characterized by plasticity and conversion between the T reg cell and effector IEL programmes 22,23 .…”

Bohemian T cell receptors: sketching the repertoires of unconventional lymphocytes

“…CD4-IELs acquire a Th1-like phenotype and are implicated in contributing to the inflammation-mediating damage in celiac disease, ulcerative colitis, and Crohn's disease, but precisely how is unknown 67,68. It was recently shown that somatic cell nuclear transfer of a TCR derived from a lamina propria Treg cell drove not only differentiation into a peripheral Treg fate, but into CD4-IELs as well, suggesting there is some level of shared specificity between them 69. Another fascinating subset of αβ IELs are known as the "natural"IELs.…”