O'Sullivan, Brendan, Pai, Saparna, Street, Shayna, Macdonald, Kelli, Gerondakis, Steve, Hill, Geoffrey, and Thomas, Ranjeny (2010) Autoreactive T Cells Escaping Thymic Deletion in REL-B Deficient Mice Depend on Dendritic Cell-encoded REL-B for Control of Autoimmunity. Clinical Immunology, 135. S134-S135.

PDF (Published Version) - Published Version Restricted to Repository staff only

Abstract

In humans and mice, autoimmunity is associated with mutations that attenuate T cell receptor (TCR) signaling capacity, which alter thymic selection, and signaling of the peripheral T cell repertoire. The RelB transcription factor controls maturation of antigen presenting cell function by dendritic cells (DCs). Similar to TCR signaling mutants, RelB-/-mice have severe T cell-dependent autoimmune disease and relative lymphopenia, but normal numbers of FoxP3+ regulatory T cells. By analysis of effector and regulatory T cell phenotype and function, distribution and function of antigen presenting cells (APCs) and DC transfer studies in RelB knockout and RelB-/-bone marrow chimeras, we addressed whether reduced capacity of thymic and peripheral APCs to signal T cells drives autoimmunity in RelB-/- mice. Th2-type RelB-/- CD44hi effector T cells, which escape thymic negative selection due to medullary atrophy and APC deficiency, are susceptible to RelB-/- Treg suppression only when signalled by wild type DCs, with enhanced costimulatory activity. Transfer of RelB-sufficient DCs, to RelB-/- mice reversed peripheral organ inflammmtory disease, Th2 cytokine over-production, thymic atrophy and lymphopenia, and rendered effector T cells susceptible to suppression by Treg cells. Thus, similar to defects in TCR signaling, autoimmunity may also result from defects in APC function. In the absence of DC-encoded RelB, progressive T cell and myeloid cell-mediated inflammation, uncontrolled by Treg cells, destroys thymus and other organs. Genetic and environmental factors control the level of RelB expression, and reduced expression is predicted to exacerbate the effect of mutations, such as PTPN22R620W that attenuate TCR signaling capacity.

Item ID:	56703
Item Type:	Article (Abstract)
ISSN:	1521661
Date Deposited:	19 Dec 2023 01:42
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 100%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
Downloads:	Total: 2
	More Statistics