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Emerging evidence is encouraging and suggests that a substantial proportion of patients without antibody responses (due to anti-CD20 therapy or other etiologies) to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines develop T cell responses. However, antigen-specific T cellular responses are notoriously difficult to assess clinically, given the lack of such assays under satisfactory CAP/CLIA regulation, and the laborious nature of the flow cytometric assessment. To evaluate the ability to apply a clinically feasible assay to measure T cellular responses to SARS-CoV-2 mRNA vaccination, we compared flow cytometric and enzyme-linked immunosorbent assay (ELISA) based assays in 24 participants treated with anti-CD20 therapy. T cellular activation (CD69 + CD137+ surface expression, i.e., activation induced markers [AIM]) and intracellular interferon gamma (INFγ) production via flow cytometry was compared to plasma Interferon Gamma Release Assay (IGRA) via ELISA. Plasma INFγ production measured by IGRA correlated with the percent of INFγ-producing AIM positive T cells, supporting the use of IGRA assay as a robust assessment of T cellular response to the SARS-CoV-2 vaccine for B-cell depleted patients that is clinically feasible, time efficient, and cost effective. [Display omitted] [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naïve CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naïve T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS. Unlabelled Image • B cell depletion in MS patients reduces memory T cells and increases naïve T cells, suggesting that T cell activation is reduced when B cells are low. • Be cell depletion in MS patients reduces CD4+ Th1 cells and increases the percentage of CD4+ regulatory T cells. • NK cell subsets change following anti-CD20 therapy, suggesting that NK cell-mediated killing of B cells has long-term consequences. [ABSTRACT FROM AUTHOR]

B cell depletion therapy has been shown to be beneficial in multiple sclerosis (MS). However, the mechanism by which B cell depletion mediates its beneficial effects in MS is still unclear. To better understand how B cell depletion may benefit patients with a disease previously thought to be primarily mediated by CD4 T cells, immune profiles were monitored in 48 patients in a phase II trial of ublituximab, a glycoengineered CD20 monoclonal antibody, at 18 time points over a year. As we previously described there was a significant shift in the percentages of T cells, NK cells, and myeloid cells following the initial dose of ublituximab, but this shift normalized within a week and these populations remained stable for the duration of the study. However, T cell subsets changed with an increase in the percentage of naïve CD4 and CD8 T cells and a decline in memory T cells. Importantly, the percentage of Th1 and CD4+GM-CSF+ T cells decreased, while the percentage of Tregs continued to increase over the year. Ublituximab not only depleted CD20+ B cells, but also CD20+ T cells. The favorable changes in the T cell subsets may contribute to the beneficial effects of B cell depletion therapy. [Display omitted] • B cell depletion causes an increase in naïve T cells, and a reciprocal reduction in memory T cells. • Th1 cells and GMCSF+CD4+ T cells, which are potentially pathogenic in MS, decline following B cell depletion therapy. • Tregs, which have the potential to suppress pathogenic T cells in MS, increase in patients on B cell depletion therapy. • Ublituximab efficiently depletes CD20+ T cells. [ABSTRACT FROM AUTHOR]

Abstract: In this study we have determined whether there is a relationship between CD38 expression on T cells, its distribution in different membrane microdomains, and T cell activation in SLE patients. The data show that CD38 expression is augmented in ex vivo CD3+, CD4+, CD8+, and CD25+ SLE T cells, which correlates with its increased insolubility in Brij 98 detergent, and its translocation into lipid rafts. Moreover, SLE T cells show an altered CD4:CD8 ratio, which is due to a decreased proportion of CD4+ T cells and a concomitant increase in the proportion of CD8+ T cells. These data are consistent with the increased CD38 expression and lipid raft formation, and the significant reduction in the CD4:CD8 ratio observed in mitogen-stimulated normal T cells as compared with that in ex vivo untouched normal T cells. Increased expression of CD38 in floating rafts from SLE T cells, or from activated normal T cells may modulate TCR signaling by providing or sequestering signaling molecules to the engaged TCR. [Copyright &y& Elsevier]