T Cell Involvement in Neuroinflammation After Traumatic Brain Injury: Implications for Therapeutic Intervention

Abstract

Background: Traumatic brain injury (TBI) is a leading cause of death and disability across all age groups worldwide. After primary mechanical head injury, a cascade of molecular changes and immunological responses occur that are necessary for supporting tissue repair but also exacerbate the secondary loss of tissue caused by excessive neuroinflammation. To date, there are no targeted treatments that ameliorate the pathological neuroinflammation that is responsible for propagating secondary injury after TBI. Recent works have highlighted the adaptive immune system's response to TBI, with mounting evidence suggesting that T cells play a critical yet understudied role in propagating secondary injury while also potentially supporting reparative processes.

Objectives: We critically review the current literature to discuss the diverse functionality of T cells in TBI including the temporospatial characteristics of their response, mechanisms of their activation, and their contributions to the overall neuroinflammatory profile. Consideration is given for additional pathological factors that may further alter these properties. We additionally summarize previous reports of therapeutic T cell modulation in this setting and identify approaches warranting additional investigation. Finally, we discuss major gaps in the existing literature and recommend future research perspectives.

Conclusion: Evidence suggests several aspects of the T cell response to TBI may serve as beneficial therapeutic targets for limiting secondary injury. Additional translational investigations are warranted and may support the development of effective therapeutic strategies for treating patients post-head trauma.

Keywords: T cells; T lymphocytes; acute brain injury; neuroinflammation; traumatic brain injury.

FIGURE 1

TCR‐dependent versus independent mechanisms of T cell activation. T cells are classically activated via TCR‐dependent mechanisms (left). Protein antigen is processed by MHC‐expressing antigen presenting cells and subsequently presented extracellularly on either MHC‐I or MHC‐II. The interaction of antigen‐loaded MHC‐I or II with the TCR‐CD3 complex on the surface of T cells and the co‐stimulatory signals CD8 or CD4, respectively, induces intracellular signaling cascades that ultimately promote cellular activation. T cells may also be activated in a TCR‐independent manner (right). Ligand cytokines and DAMPs released by other cells into the intracellular space bind to cytokine receptors or TLRs, respectively. This induces intracellular signaling to promote T cell activation distinct from the pathway initiated by the TCR complex. DAMPs, damage‐associated molecular patterns; MHC, major histocompatibility complex; TCR, T cell receptor; TLR, toll‐like receptor.

FIGURE 2

Potential mechanism of TCR‐dependent peripheral T cell recruitment after TBI. After primary mechanical injury, CNS antigens released from the parenchyma enter the meningeal lymphatics and bloodstream (1) where they are trafficked to secondary lymphoid organs like the CLNs and spleen (2). In these sites, APCs process and present the CNS antigen on MHC complexes to directly stimulate naïve T cells via the TCR (3). Chemokines concurrently released from the site of brain injury induce activated T cells to migrate into the bloodstream (4), where they home along the increasing chemokine gradient toward the brain (5) and ultimately infiltrate the parenchyma (6) to reach the site of injury. APCs, antigen presenting cells; CNS, central nervous system; CLNs, cervical lymph nodes; MHC, major histocompatibility complex; TCR, T cell receptor.

FIGURE 3

Contribution of T cell subsets to neuroinflammation in TBI. Upon successful activation, differentiation of naïve CD4+ T cells is directed by the chemokine profile of the microenvironment. Th1 and Th17 helper T cells have potent pro‐inflammatory functions in TBI, whereas Tregs have been shown to attenuate neuroinflammation. The role of Th2 helper T cells remains largely unstudied in TBI to date. CD8+ T cells exert pro‐inflammatory effects, and the functionality of γδ T cells depends on the variable portion of the γ chain of the T cell receptor.