IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an infl ammatory demyelinating disease of the central nervous system (CNS) induced in laboratory animals by active immunization with myelin antigens or by the adoptive transfer of myelin-specifi c CD4 + T cells. It is widely used as an animal model of multiple sclerosis (MS) and as a prototype of organ-specifi c autoimmunity. Until recently, EAE and MS were considered Th1 diseases, mediated by IL-12p70 -polarized, IFN-␥ -producing eff ector cells. This impression was based, in large part, on the association between clinical disease activity and expression of IFN-␥ and IL-12p40 (a subunit of IL-12p70) in CNS tissues, cerebrospinal fl uid, and circulating leukocytes ( 1 -3 ). In addition, activated macrophages are the predominant leukocyte in CNS infi ltrates of affl icted animals and patients, similar to the infi ltrates that characterize Th1-dependent hypersensitivity and antimicrobial responses in the periphery ( 4, 5 ).Recent fi ndings, however, suggest that the cytokine pathways underlying encephalitogenic T cell development and function are more complex than previously appreciated. Defi ciency of IL-17 or IL-23 (a heterodimeric monokine composed of IL-12p40 and p19 chains that expands and/or stabilizes Th17 cells) ( 6, 7 ) confers partial or complete resistance, respectively, against MOG 35-55 -induced EAE in C57BL/6 mice, whereas defi ciency of IFN-␥ or IL-12p70 does not ( 8 -10 ). Furthermore, myelin-specifi c

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

“…Other authors have shown that distinct effector-cell populations can mediate similar clinical effects in EAE [28]. Adoptive transfer of IL-12p70-or IL-23-polarized myelin-reactive T cells into naive hosts results in paralysis that is clinically indistinguishable between the two groups; the disease induced by each of these cell lines nonetheless differs in CNS chemokine expression patterns as well as in the composition and location of infiltrating leukocyte populations within the spinal cord [28].…”

“…Adoptive transfer of IL-12p70-or IL-23-polarized myelin-reactive T cells into naive hosts results in paralysis that is clinically indistinguishable between the two groups; the disease induced by each of these cell lines nonetheless differs in CNS chemokine expression patterns as well as in the composition and location of infiltrating leukocyte populations within the spinal cord [28]. In our system, we detected no differences in the characteristics or distribution of the cellular infiltrate in spinal cord tissue from EAE-affected CCR6 À/À and CCR6 1/1 mice, except for the CD4 1 T-cell population.…”

“…The cytokine profile in CCR6 À/À target tissues showed a preferential increase in proinflammatory (IL-1a, IL-6) versus downregulatory (IL-10, IL-13) transcript levels compared with WT counterparts, in accordance with the greater neurological impairment in CCR6 À/À mice. As a result, these mice show an imbalanced cytokine profile, which could account for their recovery delay and longer-lasting neurological damage.Other authors have shown that distinct effector-cell populations can mediate similar clinical effects in EAE [28]. Adoptive transfer of IL-12p70-or IL-23-polarized myelin-reactive T cells into naive hosts results in paralysis that is clinically indistinguishable between the two groups; the disease induced by each of these cell lines nonetheless differs in CNS chemokine expression patterns as well as in the composition and location of infiltrating leukocyte populations within the spinal cord [28].…”

Persistence of effector memory Th1 cells is regulated by Hopx

“…Th1 cells have been described to be more susceptible to Fas-mediated apoptosis than Th2 [14][15][16][17] and Th17 cells [18][19][20]. However, Th1 cells can be long lived and drive chronic inflammation [6][7][8][9][10][11][12][13], and can persist as effector/memory cells efficiently [24][25][26]65]. Obviously, compensatory regulatory mechanisms have to exist in those cells.…”

“…Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20].…”