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Elevated T cell receptor signaling identifies a thymic precursor to the TCR??(+)CD4(-)CD8?(-) intraepithelial lymphocyte lineage.

ABSTRACT: The origin and developmental pathway of intestinal T cell receptor ??(+) CD4(-)CD8?(-) intraepithelial lymphocytes (unconventional iIELs), a major population of innate-like resident cytolytic T cells, have remained elusive. By cloning and expressing several TCRs isolated from unconventional iIELs, we identified immature CD4(lo)CD8(lo)(DP(lo))CD69(hi)PD-1(hi) thymocytes as the earliest postsignaling precursors for these cells. Although these precursors displayed multiple signs of elevated TCR signaling, a sizeable fraction of them escaped deletion to selectively engage in unconventional iIEL differentiation. Conversely, TCRs cloned from DP(lo)CD69(hi)PD-1(hi) thymocytes, a population enriched in autoreactive thymocytes, selectively gave rise to unconventional iIELs upon transgenic expression. Thus, the unconventional iIEL precursor overlaps with the DP(lo) population undergoing negative selection, indicating that, concomitant with the downregulation of both CD4 and CD8 coreceptors, a balance between apoptosis and survival signals results in outcomes as divergent as clonal deletion and differentiation to the unconventional iIEL lineage.

SUBMITTER: McDonald BD

PROVIDER: S-EPMC4188477 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ(+)CD4(-)CD8β(-) intraepithelial lymphocyte lineage.

McDonald Benjamin D BD Bunker Jeffrey J JJ Ishizuka Isabel E IE Jabri Bana B Bendelac Albert A

Immunity 20140814 2

The origin and developmental pathway of intestinal T cell receptor αβ(+) CD4(-)CD8β(-) intraepithelial lymphocytes (unconventional iIELs), a major population of innate-like resident cytolytic T cells, have remained elusive. By cloning and expressing several TCRs isolated from unconventional iIELs, we identified immature CD4(lo)CD8(lo)(DP(lo))CD69(hi)PD-1(hi) thymocytes as the earliest postsignaling precursors for these cells. Although these precursors displayed multiple signs of elevated TCR sig ...[more]

PMID: 25131532

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Project description:The role of conventional TCR??+CD4+ or TCR??+CD8?+ single-positive (sp) T lymphocytes in adaptive immunity is well-recognized. However, non-conventional T cells expressing TCR?? or TCR?? but lacking CD4 and CD8? expression [i.e., CD4-CD8?- double-negative (dn) T cells] are thought to play a role at the interface between the innate and adaptive immune system. Dn T cells are frequent in swine, cattle or sheep and predominantly express TCR??. In contrast, TCR??+ T cells are rare in dogs. In this study, we identified a high proportion of canine dn T cells in the TCR??+ T cell population of PBMC, lymphatic and non-lymphatic organs. In PBMC, the frequency of this T cell subpopulation made up one third of the frequency of TCR??+CD4+ sp, and almost half of the frequency of TCR??+CD8?+ sp T cells (i.e., ~15% of all TCR??+ T cells). Among TCR??+CD4-CD8?- dn T cells of PBMC and tissues, FoxP3+ cells were identified indicating regulatory potential of this T cell subset. 80% of peripheral blood FoxP3+TCR??+CD4-CD8?- dn T cells co-expressed CD25, and, interestingly, also the FoxP3-negative TCR??+CD4-CD8?- dn T cells comprised ~34% CD25+ cells. Some of the FoxP3-positive TCR??+CD4-CD8?- dn T cells co-expressed GATA-3 suggesting stable function of regulatory T cells. The frequency of GATA-3 expression by FoxP3-TCR??+CD4-CD8?- dn T cells was even higher as compared with TCR??+CD4+ sp T cells (20.6% vs. 11.9%). Albeit lacking FoxP3 and CD25 expression, TCR??+CD4-CD8?- dn T cells also expressed substantial proportions of GATA-3. In addition, TCR??+CD4-CD8?- dn T cells produced IFN-? and IL-17A upon stimulation. T-bet and granzyme B were only weakly expressed by both dn T cell subsets. In conclusion, this study identifies two dn T cell subsets in the dog: (i) a large (~7.5% in Peyer's patches, ~15% in lung) population of TCR??+CD4-CD8?- dn T cells with subpopulations thereof showing an activated phenotype, high expression of FoxP3 or GATA-3 as well as production of IFN-? or IL-17A and (ii) a small TCR??+CD4-CD8?- dn T cell subset also expressing GATA-3 without production of IFN-? or IL-17A. It will be exciting to unravel the function of each subset during immune homeostasis and diseases of dogs.

Dataset Information

Elevated T cell receptor signaling identifies a thymic precursor to the TCR??(+)CD4(-)CD8?(-) intraepithelial lymphocyte lineage.

Publications

Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ(+)CD4(-)CD8β(-) intraepithelial lymphocyte lineage.

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