Proinflammatory CD20+ T cells: Their origin and therapeutic depletion in CNS-directed autoimmunity

by Jasmin Ochs
Doctoral thesis
Date of Examination:2021-03-02
Date of issue:2021-04-06
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Martin Weber
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Tobias Derfuss
Persistent Address: http://dx.doi.org/10.53846/goediss-8530

 

 

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Abstract

English

Anti-CD20 antibody (ab) treatment exhibits an unprecedented therapeutic benefit in multiple sclerosis (MS). The very fact that B cell depletion is effective in a disease that was generally considered T cell-driven was astonishing. In addition to the extensive analysis of B cells, it also led to the discovery and the consideration of CD20+ T cells in MS pathology. CD20+ T cells are described as a small population of T cells that is increased in autoimmune diseases such as MS, but little else is known. Therefore, we wanted to understand which role CD20+ T cells play in MS and dissect whether their depletion by anti CD20 abs partakes in the positive therapeutic effect. We also wanted to analyze the origin of CD20+ T cells in MS and in experimental autoimmune encephalomyelitis (EAE) as our model system. In this context, we discovered and described CD20+ T cells in mice. Since we were unable to expand the CD20+ T cell population in vitro without B cell-dependent T cell activation, we ascertained that murine CD20+ T cells cannot endogenously express CD20. As a result, we examined the hypothesis of a trogocytotic transfer of CD20 from CD20-highly expressing B cells to T cells during antigen-dependent T cell-B cell interaction. We could demonstrate in various in vitro and in vivo experiments that trogocytosis is indeed the actual origin of CD20+ T cells in mice. These results suggest that CD20 on T cells could serve as a marker for T cell activation by B cells. In EAE mice, but also in MS patients, we could determine CD20+ T cells to be predominantly proinflammatory cells, which strongly express pathogenic attributes, promoting their potential relevance in MS development and progression. The expansion of CD20+ T cells in EAE mice and MS patients and their depletion with anti CD20 antibodies in both species furthers the hypothesis of their pertinence in the disease. Ultimately, adoptive transfer experiments and the characterization of CD20+ T cells in greater detail strongly indicate their pathogenicity in EAE, respectively MS.
Keywords: CD20+ T cells; Multiple sclerosis
 
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