T cell infiltration as a novel therapeutic target in aged traumatic brain injury
Patients aged 65 years and older account for an increasing proportion of those who suffer from traumatic brain injury (TBI). Aged TBI patients experience increased morbidity and mortality compared to young TBI patients. Our prior data demonstrated that anti-CD49d antibody (aCD49d Ab), an FDA-approved drug that blocks a4 integrin, abrogates infiltration of CD8+ T-cells into the injured brain, improves survival, and attenuates neurocognitive deficits. Yet, the molecular mechanisms underlying the therapeutic effects of aCD49d Ab remained unexplored. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, we found that mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of CD8+ T cell cytotoxicity. Further, aCD49d Ab further produces a neuroprotective Th2 response and restores age-associated CD8+ T cell senescence. Our results demonstrate that targeting infiltrating CD8+ T cells with aCD49d Ab is a promising therapeutic strategy for treating TBI in aged individuals. Overall design: Aged versus young mice were subject to controlled cortical impact of traumatic brain injury followed by receving aCD49d Ab versus isotype treatmemt. Treatment was repeated every two weeks. At two months post TBI, brain cell isolated from aged versus young mouse underwent CD45+ FACS followed by 10x single cell RNA sequencing and TCR sequencing