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Abstract
We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, and diverts Vα14/Jα18 TCR transgenic thymocytes into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice mitigated their disease, suggesting that the combined defects in negative selection and iNKT cells due to altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.
Highlights
To become mature T cells, thymocytes must navigate through a complex process of selection and instruction, centered around signals received through their newly created T cell antigen receptors (TCRs)
We previously showed that if a constitutively nuclear mutant of human Histone Deacetylase 7 (HDAC7) (HDAC7-DP) is transiently expressed at normal levels during thymic T cell development but not in mature T cells, autoreactive cells that would normally die by negative selection instead exit the thymus as naıve Tconv (Kasler et al, 2012)
We noted a modest suppression of Treg (Kasler et al, 2012) and CD8aa IEL (Figure 1—figure supplement 1A), but the most striking observation we made was the near total absence of invariant Natural Killer T cells, an oligoclonal population that is reactive to a-galactosyl ceramide presented by the CD1D noncanonical MHC molecule (CD1D/aGalCer) (Kronenberg, 2014)
Summary
To become mature T cells, thymocytes must navigate through a complex process of selection and instruction, centered around signals received through their newly created T cell antigen receptors (TCRs). While the elucidation of these mechanisms decades ago established a basic conceptual framework for the creation of a competent and self-tolerant T cell repertoire, the years since have brought to light an ever-increasing variety of alternate developmental programs that produce specialized populations of mature T cells functionally distinct from Tconv These populations, critical for both effective host defense and self-tolerance, are elicited from the diverse pool of T cell precursors by specialized selection mechanisms, mostly involving strong recognition of noncanonical ligands, as in the case of NKT cells (Kronenberg, 2014), or recognition of peptide-MHC ligands at high TCR avidities near the threshold of negative selection, as in the case of nTreg or CD8aa IEL (Klein et al, 2014; Moran et al, 2011).
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