Monofunctional and Polyfunctional CD8⁺T Cell Responses to Human Herpesvirus 8 Lytic and Latency Proteins

Abstract

Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. It is postulated that CD8؉ T cell responses play an important role in controlling HHV-8 infection and preventing development of disease. In this study, we investigated monofunctional and polyfunctional CD8 ؉ T cell responses to HHV-8 lytic proteins gB (glycoprotein B) and K8.1 and latency proteins LANA-1 (latency-associated nuclear antigen-1) and K12. On the basis of our previous findings that dendritic cells (DC) reveal major histocompatibility complex (MHC) class I epitopes in gB, we used a DC-based system to identify 2 novel epitopes in gB, 2 in K8.1, 5 in LANA-1, and 1 in K12. These new HHV-8 epitopes activated monofunctional and polyfunctional CD8 ؉ T cells that produced various combinations of gamma interferon, interleukin 2, tumor necrosis factor alpha, macrophage inhibitory protein 1␤, and cytotoxic degranulation marker CD107a in healthy HHV-8-seropositive individuals. We were also able to detect HHV-8-specific CD8 ؉ T cells in peripheral blood samples using HLA A*0201 pentamer complexes for one gB epitope, one K8.1 epitope, two LANA-1 epitopes, and one K12 epitope. These immunogenic regions of viral lytic and latency proteins could be important in T cell control of HHV-8 infection.

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral IRF3 Modulates Major Histocompatibility Complex Class II (MHC-II) Antigen Presentation through MHC-II Transactivator-Dependent and -Independent Mechanisms: Implications for Oncogenesis

“…T-cell responses to KSHV-encoded latent antigens and lytic antigens have been identified in both healthy immunocompetent donors and immunocompromised patients (32)(33)(34)(35)(36)(37). Although generally weak, KSHV-specific CD8 T cells responses are more frequent, diverse, and strong in asymptomatic KSHV-infected patients than Kaposi's sarcoma patients (38).…”

Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Inhibits Major Histocompatibility Complex Class II Expression by Disrupting Enhanceosome Assembly through Binding with the Regulatory Factor X Complex

“…Hence, a disruption of the RFX complex by LANA may result in a reduced binding of NLRC5 to the MHC-I enhanceosome, thus leading to reduced expression of MHC-I genes as well. MHC-I antigen presentation is critical for the activation of CD8 ϩ T cells, which has also been shown to play an important role in controlling KSHV infections (75,76). The role of LANA in inhibiting MHC-I through this mechanism remains to be explored, but targeting of the RFX complex by KSHV appears to help the virus dodge both MHC-I and MHC-II antigen-presenting pathways and consequently evade CD4 ϩ T and CD8 ϩ T cell immunities simultaneously.…”

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

“…9 Furthermore, ex vivo stimulation of PBMCs with dendritic cells sensitized with overlapping LANA peptides has been shown to stimulate CD8 ϩ T-cell responses. 5 Using these LANA-specific CD4 ϩ clones to probe recognition of LANA-expressing cells, we found that EBV-transformed B cells, cells that have an intact class II antigen processing pathway, could efficiently process and present LANA antigens. However, when the clones were tested against most PELs, cells that natively express LANA, no recognition was seen, nor when the protein was overexpressed or fed to the PELs.…”

“…Relatively low T-cell responses to LANA and Kaposin have been described in healthy immunocompetent donors; 5,6 however, most studies have been undertaken using donors with a disrupted immune system or in disease settings, focusing on responses to LANA and Kaposin. Thus, HIV-infected patients on HAART who control KSHV have been found to make T-cell responses to LANA, MCD patients make responses comparable to HIV patients on HAART, but patients with KS disease have very weak or no detectable responses.…”

“…Potential immune targets in KS include the latent antigens, namely, the genome maintenance protein LANA that is expressed in all infected cells and malignancies, the viral cyclin vCyclin, the antiapoptotic multifunctional protein vFLIP, and Kaposin. PELs and infected cells in MCD also express at least 2 other proteins, the viral IL-6 and the immunomodulatory and antiapoptotic protein vIRF3.Relatively low T-cell responses to LANA and Kaposin have been described in healthy immunocompetent donors; 5,6 however, most studies have been undertaken using donors with a disrupted immune system or in disease settings, focusing on responses to LANA and Kaposin. Thus, HIV-infected patients on HAART who control KSHV have been found to make T-cell responses to LANA, MCD patients make responses comparable to HIV patients on HAART, but patients with KS disease have very weak or no detectable responses.…”