Extracellular vesicles in human semen modulate antigen-presenting cell function and decrease downstream antiviral T cell responses

Human semen contains trillions of extracellular vesicles (SEV) similar in size to sexually transmitted viruses and loaded with potentially bioactive miRNAs, proteins and lipids. SEV were shown to inhibit HIV and Zika virus infectivity, but whether SEV are able also to affect subsequent immune responses is unknown. We found that SEV efficiently bound to and entered antigen-presenting cells (APC) and thus we set out to further dissect the impact of SEV on APC function and the impact on downstream T cell responses. In an APC–T cell co-culture system, SEV exposure to APC alone markedly reduced antigen-specific cytokine production, degranulation and cytotoxicity by antigen-specific memory CD8+ T cells. In contrast, inhibition of CD4+ T cell responses required both APC and T cell exposure to SEV. Surprisingly, SEV did not alter MHC or co-stimulatory receptor expression on APCs, but caused APCs to upregulate indoleamine 2,3 deoxygenase, an enzyme known to indirectly inhibit T cells. Thus, SEV reduce the ability of APCs to activate T cells. We propose here that these immune-inhibitory properties of SEV may be intended to prevent immune responses against semen-derived antigens, but can be hi-jacked by genitally acquired viral infections to compromise adaptive cellular immunity.