Asymptomatic memory CD8⁺T cells

Abstract

Generation and maintenance of high quantity and quality memory CD8(+) T cells determine the level of protection from viral, bacterial, and parasitic re-infections, and hence constitutes a primary goal for T cell epitope-based human vaccines and immunotherapeutics. Phenotypically and functionally characterizing memory CD8(+) T cells that provide protection against herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections, which cause blinding ocular herpes, genital herpes, and oro-facial herpes, is critical for better vaccine design. We have recently categorized 2 new major sub-populations of memory symptomatic and asymptomatic CD8(+) T cells based on their phenotype, protective vs. pathogenic function, and anatomical locations. In this report we are discussing a new direction in developing T cell-based human herpes vaccines and immunotherapeutics based on the emerging new concept of "symptomatic and asymptomatic memory CD8(+) T cells."

Phenotypic and Functional Characterization of Herpes Simplex Virus Glycoprotein B Epitope-Specific Effector and Memory CD8+T Cells from Symptomatic and Asymptomatic Individuals with Ocular Herpes

“…The different characteristics of T CM and T EM cells suggest that they play different roles in recall responses and containment of herpes infection and disease (26,(28)(29)(30). We hypothesize that ASYMP individuals develop more of the protective HSV-specific CD8 ϩ T EM cells, while SYMP patients develop more of the nonprotective (or maybe pathogenic) HSV-specific CD8 ϩ T CM cells (31,32).…”

“…In B6 mice, an immunodominant CD8 ϩ T cell epitope, gB 498 -505 , achieved at least partial protection against herpes infection and disease (8,12,22,23). Considering the wealth of data addressing the phenotype and function of HSV-1 gB 498 -505 epitope-specific CD8 ϩ T cells in mice (4-6, 24, 25), it is surprising how few reports exist characterizing the phenotype and function of human epitope-specific "protective" CD8 ϩ T cells from HSV-seropositive healthy ASYMP individuals, who appear to have acquired a "natural" protection (13,26). This information is necessary for the successful design of an effective T cell-based therapeutic vaccine strategy.…”

“…While memory CD8 ϩ T cell subpopulations are heterogeneous in terms of phenotype, function, and anatomical distribution, they can generally be divided into two major subsets: effector memory CD8 ϩ T cells (T EM cells) and central memory CD8 ϩ T cells (T CM cells) (26,27). The different characteristics of T CM and T EM cells suggest that they play different roles in recall responses and containment of herpes infection and disease (26,(28)(29)(30).…”

“…Similar to the case for T-bet and Eomes, levels of the transcriptional regulators ID1 (inhibitor of differentiation 1), ID3, Blimp-1 (prdm1), Bcl-2, and TCF, which play critical roles in the effector-to-memory CD8 ϩ T cell transition (39,59), were also high in HSV-specific CD8 ϩ T cells from ASYMP individuals compared to HSV-specific CD8 ϩ T cells from SYMP patients (data not shown). It is likely that the concerted action of T-bet, Eomes, and other transcription factors results in the development in ASYMP individuals of fully differentiated CD8 ϩ T EM cells that migrate to inflamed tissues (i.e., eyes and sensory ganglia) following antigen recognition and secrete IFN-␥ and CD107 a/b , and/or release cytotoxic granules such as GzmB and perforin (26,60).…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…To our knowledge, this is the first study to show the differential expression of transcription factors in VP13/14-specific human memory CD8 ϩ T cells among HLA-A*02:01-positive, HSV-1-seropositive SYMP and ASYMP individuals. It is likely that the concerted action of T-bet, Eomes, and other transfection factors results in the development in ASYMP individuals of fully differentiated CD8 ϩ T EM cells that migrate to inflamed tissues (i.e., eyes and sensory ganglia) following antigen recognition and secrete IFN-␥ and/or release cytotoxic granules that contain GzmB and perforin (68,69).…”