Do CD8 suppressor cells mediate the protective effect of CD20 depletion

Howlett-Prieto Q, Feng X, Kramer JF, Kramer KJ, Houston TW, Reder AT. Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis. Mult Scler. 2021:13524585211003301. doi: 10.1177/13524585211003301. Epub ahead of print. PMID: 33783270.

Objective: To determine the effect of long-term anti-CD20 B-cell-depleting treatment on regulatory T cell immune subsets that are subnormal in untreated MS patients.

Methods: 30 clinically stable MS patients, before and over 38 months of ocrelizumab treatment, were compared to 13 healthy controls, 29 therapy-naïve MS, 9 interferon-β-treated MS, 3 rituximab-treated MS, and 3 rituximab-treated patients with other autoimmune inflammatory diseases. CD8, CD28, CD4, and FOXP3 expression in peripheral blood mononuclear cells was quantitated with flow cytometry.

Results: CD8⁺ CD28^– regulatory cells rose from one-third of healthy control levels before ocrelizumab treatment (2.68% vs 7.98%), normalized by 12 months (13.5%), and rose to 2.4-fold above healthy controls after 18 months of ocrelizumab therapy (19.0%). CD4⁺ FOXP3⁺ regulatory cells were lower in MS than in healthy controls (7.98%) and showed slight long-term decreases with ocrelizumab. CD8⁺ CD28^– and CD4⁺ FOXP3⁺ regulatory T cell percentages in IFN-β-treated MS patients were between those of untreated MS and healthy controls.

Interpretation: Long-term treatment with ocrelizumab markedly enriches CD8⁺ CD28^– regulatory T cells and corrects the low levels seen in MS before treatment, while slightly decreasing CD4⁺ FOXP3+ regulatory T cells. Homeostatic enrichment of regulatory CD8 T cells provides a mechanism, in addition to B cell depletion, for the benefits of anti-CD20 treatment in MS.

How do CD20-depleting antibodies work? Is the T cell the important thing, I suspect the the simple answer is probably No….but in my new reconciliation persona, you have to say it is possible. This paper introduces us to CD8 regulators. We have heard or an endless stream of CD4 Treg (T regulatory cell) papers over the last decade or more, but historically the regulators were origially called CD8 T suppressor cells. This paper suggests that CD8 (suppressor) cells may contribute to to the action of anti-CD20 antibodies. We have suggested one way you get benefit is from depleting the disease causing cells. As the regulatory cells repopulate quicker than the disease causing cells, when they return they come back into a regulated environment and disease is controlled. This may be too simplistic, but it is a easy way to see how disease is controlled by certain treatments. However, these events wont’t be occuring in isolation and CD4 Tregs and B regulatory cells may have their part to play.

We have previously suggested that CD8 regulatory cell depletion may be part of the explanation for autoimmunity after CD52 (alemtuzumab) T and B cell depletion. Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis.von Kutzleben S, Pryce G, Giovannoni G, Baker D.Immunology. 2017;150(4):444-455.