Regulatory T cells in intracerebral hemorrhage: mechanisms of immunomodulation and therapeutic potential
TL;DR
It is proposed that Treg-centered immunomodulation represents a promising but still underdeveloped therapeutic strategy for improving recovery after ICH and particular attention to emerging approaches such as antigen-specific CAR-Treg cells and gut–brain axis modulation.
Abstract
Intracerebral hemorrhage (ICH) induces profound secondary brain injury, largely driven by dysregulated neuroinflammation, yet effective immunomodulatory therapies remain limited. Regulatory T (Treg) cells, a specialized subset of CD4+ T cells essential for immune tolerance and tissue repair, have emerged as critical modulators of post-ICH inflammation and recovery. Following ICH, Treg responses undergo dynamic temporal and spatial changes in the peripheral immune compartment and injured brain, where they may exert neuroprotective effects through multiple mechanisms, including the production of anti-inflammatory cytokines such as IL-10, TGF-β, and IL-35, regulation of microglia/macrophage activation toward reparative phenotypes, promotion of oligodendrocyte precursor cell differentiation, and attenuation of neurotoxic astrogliosis partly through amphiregulin-dependent pathways. Clinical observations suggest that alterations in circulating Treg populations are associated with neurological outcomes after ICH, although these relationships appear to be influenced by disease severity, sampling time, and patient heterogeneity. In experimental models, strategies that enhance Treg number or function, including adoptive Treg transfer, low-dose IL-2, rapamycin, and rCCL17, have been shown to reduce neuroinflammation, limit brain injury, and improve neurological recovery. However, key translational challenges remain, including the optimal therapeutic window, CNS-targeted delivery, antigen specificity, long-term phenotypic stability, and the influence of aging and comorbidities on Treg function. This review synthesizes current evidence regarding Treg dynamics, mechanisms, and therapeutic potential in ICH, with particular attention to emerging approaches such as antigen-specific CAR-Treg cells and gut–brain axis modulation. By integrating mechanistic insights with translational considerations, we propose that Treg-centered immunomodulation represents a promising but still underdeveloped therapeutic strategy for improving recovery after ICH.