Identification and characterization of HIV-specific resident memory CD8 + T cells in human lymphoid tissue

Abstract

<p class="first" id="P2">Current paradigms of CD8 ⁺ T cell-mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL) and LTs in different species, we show that many LT memory CD8 ⁺ T cells bear phenotypic, transcriptional and epigenetic signatures of resident memory T cells (T _RMs). Unlike their circulating counterparts in blood or TDL, the majority of total and follicular HIV-specific CD8 ⁺ T cells in LTs also resemble T _RMs. Moreover, high frequencies of HIV-specific CD8 ⁺ T _RMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA-seq analysis confirmed that HIV-specific T _RMs are enriched for effector-related immune genes and signatures compared to HIV-specific non-T _RMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8 ⁺ T cell responses resident within LTs. </p>