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 (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs. Moreover, high frequencies of HIV-specific CD8+ TRMs 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 sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs 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.
Bibliographical noteFunding Information:
was supported by R01/R56 grants from the NIH (AI076066, AI118694, and AI106481 to M.R.B.), the Martin Delaney Collaboratory: Towards an HIV1 Cure (BEAT: AI126620; DARE: AI096109 and A127966), the Penn Center for AIDS Research (CFAR) (AI045008), the amfAR Institute for HIV Cure Research (amfAR 109301 to S.G.D.), the University of California, San Francisco/ Gladstone Institute of Virology and Immunology CFAR to the SCOPE cohort (P30 AI027763 to S.G.D.), K22AI112570 to G.V., and the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH (D.C.D.). M.B. is funded through the Swedish Research Council (Dnr 53720146829), Karolinska Institutet, Magnus Bergvall, and Lars Hiertas Stiftelse. D.A.P. is a Welcome Trust Senior Investigator. D.d.A. and L.F.S. were supported by a Medical Research Grant from the W. W. Smith Charitable Trust Foundation and the Penn CFAR Grant. R.S.H. is funded by K08 grant (AI114852). G.R.T. is funded by the Mexican Government (Comisión de Equidad y Género de las Legislaturas LXLXI, y Comisión de Igualdad de Género de la Legislatura LXII de la H. Cámara de Diputados de la República Mexicana).