Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity
Anthony J. Slavin, … , Elizabeth K. Bikoff, Scott S. Zamvil
Anthony J. Slavin, … , Elizabeth K. Bikoff, Scott S. Zamvil
Published October 15, 2001
Citation Information: J Clin Invest. 2001;108(8):1133-1139. https://doi.org/10.1172/JCI13360.
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Article

Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity

Abstract

The role of processing in antigen (Ag) presentation and T cell activation in experimental allergic encephalomyelitis (EAE) was evaluated in wild-type mice, mice that selectively express either Ii p31 or p41, and mice completely deficient in Ii or H-2M. We demonstrate that processing of myelin oligodendrocyte glycoprotein (MOG) is required for presentation of the dominant encephalitogenic MOG epitope, p35-55. Ii p31- and p41-expressing mice developed EAE with similar incidence to wild-type mice, although p41 mice had a more severe course. Ag-presenting cells (APCs) from Ii- or H-2M–deficient mice could present p35-55, but not MOG, demonstrating that these APCs could not process native MOG. Ii- and H-2M–deficient mice were not susceptible to EAE by immunization with p35-55 or MOG or by adoptive transfer of encephalitogenic T cells. However, CD4+ T cells from p35-55–immunized H-2M–deficient mice proliferated, secreted IFN-γ, and transferred EAE to wild-type, but not H-2M–deficient, mice. Thus, EAE resistance in H-2M–deficient mice is not due to an inability of APCs to present p35-55, or an intrinsic defect in the encephalitogenic T cell repertoire, but reflects a defect in APC function. Our results indicate that processing is required for initial Ag presentation and CNS T cell activation and suggest that autopathogenic peptides of CNS autoantigen may not be readily available for presentation without processing.

Authors

Anthony J. Slavin, Jeanne M. Soos, Olaf Stuve, Juan C. Patarroyo, Howard L. Weiner, Adriano Fontana, Elizabeth K. Bikoff, Scott S. Zamvil

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Presentation of native MOG requires endocytic processing. Ii- or H-2M–de...
Presentation of native MOG requires endocytic processing. Ii- or H-2M–deficient APCs can present p35-55 (a), but not native MOG (b), to encephalitogenic p35-55–specific T cells. (c) Paraformaldehyde-fixed wild-type APCs can present p35-55, but not native MOG, to p35-55–specific T cells. (d) Chloroquine-treated wild-type APCs can present p35-55 but do not present native MOG to p35-55–specific T cells. Irradiated splenocytes were cultured with p35-55–specific T cells in the presence of p35-55, native MOG, or no Ag, as described in Methods. Proliferative responses were measured by [3H]thymidine incorporation. For APC fixation, splenocytes were treated with paraformaldehyde, then cultured with p35-55–specific T cells in the presence of either p35-55, native MOG (50 μg/ml), or no Ag (see Methods). Irradiated wild-type splenocytes (b), tested at the same time as paraformaldehyde-fixed wild-type APCs (c), stimulated T cell proliferation using native MOG. For chloroquine treatment (d), APCs were treated with 75 μM chloroquine for 75 minutes before the addition of Ag and T cells (see Methods).