Gut-Homing Delta 42pd1(+)V Delta 2 T Cells Promote Innate Mucosal Damage Via Tlr4 During Acute Hiv Type 1 Infection

The innate immune cells underlying mucosal inflammatory responses and damage during acute HIV-1 infection remain incompletely understood. Here, we report a V delta 2 subset of gut-homing gamma delta T cells with significantly upregulated Delta 42PD1 (a PD1 isoform) in acute (similar to 20%) HIV-1 patients compared to chronic HIV-1 patients (similar to 11%) and healthy controls (similar to 2%). The frequency of Delta 42PD1(+)V delta 2 cells correlates positively with plasma levels of pro-inflammatory cytokines and fatty-acid-binding protein before detectable lipopolysaccharide in acute patients. The expression of Delta 42PD1 can be induced by in vitro HIV-1 infection and is accompanied by high co-expression of gut-homing receptors CCR9/CD103. To investigate the role of Delta 42PD1(+)V delta 2 cells in vivo, they were adoptively transferred into autologous humanized mice, resulting in small intestinal inflammatory damage, probably due to the interaction of Delta 42PD1 with its cognate receptor Toll-like receptor 4 (TLR4). In addition, blockade of Delta 42PD1 or TLR4 successfully reduced the cytokine effect induced by Delta 42PD1(+)V delta 2 cells in vitro, as well as the mucosal pathological effect in humanized mice. Our findings have therefore uncovered a Delta 42PD1-TLR4 pathway exhibited by virus-induced gut-homing V delta 2 cells that may contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Delta 42PD1(+)V delta 2 cells may serve as a target for the investigation of diseases with mucosal inflammation.