Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization

Abstract

An accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCRαβ-mediated signaling and activation thresholds, on CD4+CD8+ TCRαβlo/hi thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCRαβhi thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16INK4a accumulation). The higher circulating level of TNF-α in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.

Immune Thymic Profile of the MOG-Induced Experimental Autoimmune Encephalomyelitis Mouse Model

“…Of interest, altered thymic activity had already been suggested in relapse-remitting MS patients ( 23 ) and thymic atrophy was also found in other MS models, namely the cuprizone model ( 38 ), in A.SW mice with primary-progressive EAE ( 39 ) and also, recently, in rat EAE models ( 40 ). Herein we also showed thymic atrophy accompanied by decreased percentage of viable cells, that could result from apoptotic cell death, as observed in the rat EAE models ( 40 ).…”

Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases

“…However, the loss of CD28 could also be ascribed, apart from repeated TCR activation, to enhanced action of proinflammatory cytokines (TNF-α and IL-6) [248]. Accordingly, CD4+CD28-T cells are shown to accumulate with development of chronic inflammatory autoimmune diseases, including MS and EAE [45,241,242,249,250]. Our data showed that CD4+CD28-T cell accumulation in EAE rats could also be ascribed to thymic atrophy evoked by the increased blood levels of the proinflammatory cytokines [45].…”

“…To add to complexity of thymic involution are data indicating that, in both humans and experimental animals, development of chronic inflammatory autoimmune diseases, including MS/EAE, leads to thymic atrophy [45,[67][68][69][70][71]. Our research in DA rats immunized for EAE [45] linked this phenomenon to the disease-induced rise in the circulating levels of interleukin (IL)− 6 and tumor necrosis factor (TNF)-α, the cytokines causally linked with thymic atrophy [72][73][74].…”

“…Consequently, above the age of 85 the thymus contributes < 1% of total T-cell generation, so these subjects rely on peripheral cell proliferation to repopulate T-cell compartment [40]. In experimental animals, genetic factors are also shown to play a significant role in determining the initial thymic size and the rate of its involution [41][42][43][44][45]. This has been associated with strain specificities in development of immune-mediated diseases in old age [41,44].…”

“…To add to complexity of thymic involution are data indicating that, in both humans and experimental animals, development of chronic inflammatory autoimmune diseases, including MS/EAE, leads to thymic atrophy [45,[67][68][69][70][71]. Our research in DA rats immunized for EAE [45] linked this phenomenon to the disease-induced rise in the circulating levels of interleukin (IL)− 6 and tumor necrosis factor (TNF)-α, the cytokines causally linked with thymic atrophy [72][73][74]. Differently from some previous speculations [70], this research suggested that thymic involution associated with chronic inflammation does not lead per se to overt autoimmune disease, but perpetuates the autoimmune diseases Considering the main focus of the review, in the next subsections the putative influence of aging and sex on thymic negative selection and Treg generation is addressed.…”