The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces

Obesity has become a major public health crisis given its rampant growth and association with an increased risk for cancer. Cancer patients who present with obesity tend to have increased tumor burden and decreased T-cell function, yet it remains unclear how obesity compromises T-cell mediated immunity. To address this, we modeled the adipose niche using the secretome of cultured adipocytes and assessed the impact of these factors on T-cell function. We found that these secretomes altered antigen-specific T-cell receptor triggering and activation. RNA-sequencing analysis identified changes in cytoskeletal regulation and actin polymerization in T-cells exposed to the adipocyte secretome. Molecular force measurements were consistent and showed that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex. Conversely, exposure to the control stromal cell secretome lead to enhanced TCR forces. These results were then validated in diet-induced obese mice and human donor T-cells. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.