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.
Highlights
The thymus is the primary organ providing microenvironment for T-cell development
The study complements our previous research exploring strain differences in peripheral and target-tissue immune responses to immunization for EAE [42,69] by providing insight into immunization-induced changes in thymopoiesis. It showed that immunization with syngeneic spinal cord (SC) homogenate in complete Freund’s adjuvant (CFA) leads to different changes in the thymus and the peripheral T-cell compartment in DA rats developing clinical signs of EAE, and in AO rats, which did not develop clinically manifested EAE
Only a modest thymic atrophy and decrease in the thymocyte yield were found in AO rats which failed to develop clinical signs of EAE
Summary
The thymus is the primary organ providing microenvironment for T-cell development. The continual output of mature T cells to the periphery maintains the diversity of the peripheral Tcell repertoire [1]. The thymus regulates T-cell homeostasis by clonal deletion of self-reactive effector T cells during negative selection [2,3] This process is not immaculate and some autoreactive cells inevitably escape to the periphery. Homeostatic proliferation of autoreactive T cells has been associated with higher propensity for development of autoimmunity in the elderly [9,10] This does not translate into an increased incidence of autoimmune diseases in aging [11]. This phenomenon was associated with an aging-related expansion of protective T-cell regulatory mechanisms in the periphery [11,12] and age-related intrinsic Tcell changes underlying their functional erosion [13]
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