Immunologists are rather dogmatic and prescriptive and the mantra these days is that disease is driven by TH17 CD4 T cells and it is controled by T regulatory cells….I say Yarn because this is the current dogma and we get fed this idea over and over again. There are studies that look at T reg function such as the MAGNIFY study, but it is interesting why B cells were not really mentioned when their depletion is a simple explanation for efficacy…maybe it isnt
Cammarata I, Sartori G, Giacomelli T, Pinna V, Pinzon Grimaldos A, De Rosa G, Matarese G, Procaccini C, Mishra D, Di Mitri D, Gasperini C, Guerrera G, Sambucci M, Battistini L, Piconese S. Treg Susceptibility to Cladribine-Induced Depletion Correlates With Therapy Response in Patients With Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2026 Jan;13(1):e200521. doi: 10.1212/NXI.0000000000200521.
Background and objectives: Immune reconstitution therapies for multiple sclerosis (MS) are based on selective lymphocyte reduction, followed by repopulation and rescue of immune tolerance. Among these therapies, cladribine is an adenosine analog that interferes with cell division and depletes several lymphocyte subtypes. Regulatory T cells (Tregs), physiologically devoted to immune suppression, are dysfunctional in the context of MS. In this study, we explored the effects of cladribine on Treg dynamics and phenotype.
Methods: In vivo, deep immunophenotyping was conducted on peripheral blood of patients with MS (n = 11), longitudinally collected before and after 6 and 12 months of cladribine therapy. In vitro, expanded Tregs were treated with cladribine and analyzed for their phenotypic, molecular, and metabolic profiles.
Results: In vivo, Tregs were overall less sensitive than conventional T cells (Tconvs) to the depleting effects of cladribine. This phenomenon was particularly evident in the subset of the resting (rest) Tregs. At baseline, while activated (act) Tregs presented markers of proliferation, senescence, and survival, restTregs highly expressed the antiapoptotic protein Bcl2 and the quiescence marker Bach2. In vitro, cladribine strongly reduced Treg viability while inducing a program of senescence and dysfunction and compromising their metabolic fitness. When Treg dynamics were analyzed ex vivo in relation to neuroinflammation and response to therapy, restTregs exhibited resistance to depletion in nonresponders, in association with increasing expression of Bcl2.
Discussion: These results indicate that the efficacy of cladribine therapy may require reduction and repopulation of the Treg compartment, an event that may be hindered by restTreg resistance, which is supported by antiapoptotic signals.
Source: multiple-sclerosis-research.org