Abstract
A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence. We also demonstrate that Ly6C expression on Treg in a steady state is either up- or downregulated depending on relative amounts of tonic TCR signals derived from its contacts with self-ligands. Interestingly, peripheral appearance and maintenance of these Ly6C-expressing Treg cells largely differed in an age-dependent manner, with their proportion being continuously increased from perinatal to young adult period but then being gradually declined with age. The reduction of Ly6C+ Treg in the aged mice was not due to their augmented cell death but rather resulted from downregulation of Ly6C expression. The Ly6C downregulation was accompanied by proliferation of Ly6C+ Treg cells and subsequent change into Ly6C− effector Treg with concomitant restoration of immune-suppressive activity. Importantly, we found that this phenotypic and functional change of Ly6C+ Treg is largely driven by conventional effector T cell population. Collectively, these findings suggest a potential cross-talk between peripheral Treg subsets and effector T cells and provides better understanding for Treg homeostasis and function on maintaining self-tolerance.
Highlights
CD4 T regulatory (Treg) cells are well defined for their potent immune-suppressive activity and establishment of self-tolerance, and are known to develop in the thymus as a result of positive selection from their thymic precursor cells (CD4+ CD8+ double-positive thymocytes) by relatively a high affinity/avidity of T cell receptor (TCR) interactions with self-peptide-major histocompatibilityHomeostasis of Peripheral Ly6C+ Treg Cells complex II ligands, which is referred to as thymic Treg and constitutes a major population of peripheral Treg pools under steady state (1, 2)
We demonstrated that generation and maintenance of Ly6C+ Treg cells in the peripheral lymphoid organs are regulated by a unique mechanism distinctly different from those of Ly6C− Treg populations
Our findings imply an existence of a homeostatic cross-talk between peripheral Treg pools and conventional effector T cells and highlight a physiological importance of Ly6C+ Treg subset for the maintenance of self-tolerance
Summary
CD4 T regulatory (Treg) cells are well defined for their potent immune-suppressive activity and establishment of self-tolerance, and are known to develop in the thymus as a result of positive selection from their thymic precursor cells (CD4+ CD8+ double-positive thymocytes) by relatively a high affinity/avidity of T cell receptor (TCR) interactions with self-peptide-major histocompatibilityHomeostasis of Peripheral Ly6C+ Treg Cells complex II (self-pMHC) ligands, which is referred to as thymic (or natural) Treg (tTreg) and constitutes a major population of peripheral Treg pools under steady state (1, 2). Physiological importance of the relatively high self-reactivity of tTreg has been demonstrated for their thymic deve lopment and for their peripheral survival and function (3) It is, possible that the defined phenotypic and functional heterogeneity within peripheral Treg populations might relate to their relative difference in the extent of TCR signaling for which they receive from interactions with self-ligands under steady state. This study showed that despite the remaining naive Treg cells persisted in the absence of tonic TCR signaling, these cells were not functional and failed to control conventional T cell activation and proliferation, suggesting an impaired immunesuppressive capacity of naive Treg cells (3) These prior observations provide strong evidence for differential dependency of self-reactivity of Treg populations on their peripheral homeostasis, whether and how these features relate to contribute to peripheral Treg pool’s heterogeneity in their survival, maintenance, and immune-suppressive function has not been fully understood
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