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Programmed cell death 1 and Helios distinguish TCR-??+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells.

ABSTRACT: TCR-??(+) double-negative (DN; CD4(-)CD8(-)) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8(+) cells. However, the conditions that govern the loss of CD8 expression after Ag encounter are unknown. In this study, we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate Ags as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate Ag is sensed as self. This process is restricted to tissues where the Ag is present. We also show that DN T cells derived from self-reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated with self-Ag encounter.

SUBMITTER: Rodriguez-Rodriguez N

PROVIDER: S-EPMC4503929 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Publications

Programmed cell death 1 and Helios distinguish TCR-αβ+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells.

Rodríguez-Rodríguez Noé N Apostolidis Sokratis A SA Penaloza-MacMaster Pablo P Martín Villa José Manuel JM Barouch Dan H DH Tsokos George C GC Crispín José C JC

Journal of immunology (Baltimore, Md. : 1950) 20150330 9

TCR-αβ(+) double-negative (DN; CD4(-)CD8(-)) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8(+) cells. However, the conditions that govern the loss of CD8 expression after Ag encounter are unknown. In this study, we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate Ags as self or in the context of infection. We ...[more]

PMID: 25825451

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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

Programmed cell death 1 and Helios distinguish TCR-??+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells.

Publications

Programmed cell death 1 and Helios distinguish TCR-αβ+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells.

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