Multiple sclerosis is considered a disease of complex autoimmune aetiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFNγ+ cells dominate disease initiation with IL-17+ cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFNγ responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFNγ driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFNγ cytokine production by CD4 and CD8 cells, but not IL-17 responses.
Lowther DE, Chong DL, Ascough S, Ettorre A, Ingram RJ, Boyton RJ, Altmann DM. Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response. Acta Neuropathol. 2013 Aug. [Epub ahead of print]
Immunologists have spent the first part of the the T helper cell phenotypes claiming Th1 were the central problem, then Th17 were discovered and this has become flavour of the month and the central problem. This study takes a step back and points the finger at Th1 rather than Th17 cells. However, taking a step back on many EAE studies and the IL-17 inhibition is not that successful. So we have to be cautious about accepting dogma. However inhibiting Interleukin 17 may offer some benefit in MS…we will have to see.