Bolstering the Number and Function of HSV-1-Specific CD8 + Effector Memory T Cells and Tissue-Resident Memory T Cells in Latently Infected Trigeminal Ganglia Reduces Recurrent Ocular Herpes Infection and Disease

• Published in: The Journal of immunology (1950) Vol. 199; no. 1; pp. 186 - 203
• Main Authors: Khan, Arif A, Srivastava, Ruchi, Chentoufi, Aziz A, Kritzer, Elizabeth, Chilukuri, Sravya, Garg, Sumit, Yu, David C, Vahed, Hawa, Huang, Lei, Syed, Sabrina A, Furness, Julie N, Tran, Tien T, Anthony, Nesburn B, McLaren, Christine E, Sidney, John, Sette, Alessandro, Noelle, Randolph J, BenMohamed, Lbachir
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01-07-2017
• Subjects: Activation; Adult; Aged; Animals; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - physiology; Chemokine CXCL10 - immunology; Cornea; CXCL10 protein; Effector cells; Epitopes; Epitopes - chemistry; Epitopes - immunology; Epitopes - isolation & purification; Epitopes, T-Lymphocyte - immunology; Eye diseases; Female; Ganglia; Genomes; Herpes simplex; Herpesvirus 1, Human - immunology; Histocompatibility antigen HLA; Humans; Immunization; Immunologic Memory; Immunological memory; Interferon; Keratitis, Herpetic - immunology; Keratitis, Herpetic - therapy; Keratitis, Herpetic - virology; Latency; Latent infection; Lymphocytes; Lymphocytes T; Male; Medical innovations; Memory cells; Mice; Mice, Transgenic; Middle Aged; Recurrence; Recurrent infection; Rodents; Sensory neurons; Transgenic mice; Trigeminal ganglion; Trigeminal Ganglion - cytology; Trigeminal Ganglion - immunology; Trigeminal Ganglion - virology; Virus Latency; Young Adult; γ-Interferon
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700145

HSV type 1 (HSV-1) is a prevalent human pathogen that infects >3.72 billion individuals worldwide and can cause potentially blinding recurrent corneal herpetic disease. HSV-1 establishes latency within sensory neurons of trigeminal ganglia (TG), and TG-resident CD8
T cells play a critical role in preventing its reactivation. The repertoire, phenotype, and function of protective CD8
T cells are unknown. Bolstering the apparent feeble numbers of CD8
T cells in TG remains a challenge for immunotherapeutic strategies. In this study, a comprehensive panel of 467 HLA-A*0201-restricted CD8
T cell epitopes was predicted from the entire HSV-1 genome. CD8
T cell responses to these genome-wide epitopes were compared in HSV-1-seropositive symptomatic individuals (with a history of numerous episodes of recurrent herpetic disease) and asymptomatic (ASYMP) individuals (who are infected but never experienced any recurrent herpetic disease). Frequent polyfunctional HSV-specific IFN-γ
CD107
CD44
CD62L
CD8
effector memory T cells were detected in ASYMP individuals and were primarily directed against three "ASYMP" epitopes. In contrast, symptomatic individuals have more monofunctional CD44
CD62L
CD8
central memory T cells. Furthermore, therapeutic immunization with an innovative prime/pull vaccine, based on priming with multiple ASYMP epitopes (prime) and neurotropic TG delivery of the T cell-attracting chemokine CXCL10 (pull), boosted the number and function of CD44
CD62L
CD8
effector memory T cells and CD103
CD8
tissue-resident T cells in TG of latently infected HLA-A*0201-transgenic mice and reduced recurrent ocular herpes following UV-B-induced reactivation. These findings have profound implications in the development of T cell-based immunotherapeutic strategies to treat blinding recurrent herpes infection and disease.