Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

TitleDifferential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.
Publication TypeJournal Article
Year of Publication2023
AuthorsShinoda K, Li R, Rezk A, Mexhitaj I, Patterson KR, Kakara M, Zuroff L, Bennett JL, von B├╝dingen H-C, Carruthers R, Edwards KR, Fallis R, Giacomini PS, Greenberg BM, Hafler DA, Ionete C, Kaunzner UW, Lock CB, Longbrake EE, Pardo G, Piehl F, Weber MS, Ziemssen T, Jacobs D, Gelfand JM, Cross AH, Cameron B, Musch B, Winger RC, Jia X, Harp CT, Herman A, Bar-Or A
JournalProc Natl Acad Sci U S A
Volume120
Issue3
Paginatione2207291120
Date Published2023 Jan 17
ISSN1091-6490
KeywordsAntigens, CD20, CD8-Positive T-Lymphocytes, Flow Cytometry, Humans, Leukocytes, Mononuclear, Multiple Sclerosis, Recurrence
Abstract

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20CD8 T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20CD8 T cells had a greater contribution to treatment-associated changes in the CD8 T cell pool than was the case for CD4 T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20CD8 T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19CD24CD38 with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20CD8 T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8 T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

DOI10.1073/pnas.2207291120
Alternate JournalProc Natl Acad Sci U S A
PubMed ID36634138
PubMed Central IDPMC9934304
Grant ListR01 CA227473 / CA / NCI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
UM1 AI144288 / AI / NIAID NIH HHS / United States
P01 AI039671 / AI / NIAID NIH HHS / United States
R25 NS079193 / NS / NINDS NIH HHS / United States
P50 CA121974 / CA / NCI NIH HHS / United States
U19 AI089992 / AI / NIAID NIH HHS / United States
P01 AI073748 / AI / NIAID NIH HHS / United States

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