Hantaan Virus Infection Induces Both Th1 and ThGranzyme B+ Cell Immune Responses That Associated with Viral Control and Clinical Outcome in Humans

Abstract

Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4+T cells in viral control have been extensively studied. However, the contribution of CD4+T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4+T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B+ cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4+T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4+T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4+T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127hi) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4+T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4+T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection.

Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice

“…This notion is supported by evidence that hantavirus-specific T cells play a critical role in the control of virus infection (17)(18)(19). Our previous results have demonstrated that the T-cell response during the acute stage of HFRS in patients is characterized by vigorous cytotoxic T cell (CTL) responses and multifunctional T helper (Th) cell responses against HTNV infection (20,21). Patients with milder severities of HFRS typically mount vigorous HTNV-specific CD4 + and CD8 + T-cell responses directed against the epitopes of HTNV, whereas patients with severe or critical HFRS tend to have weak and narrowly focused T-cell responses (20)(21)(22).…”

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

“…Screening of CD4 responses with peptide pools derived from the NTNV glycoprotein revealed a subset of virus-specific CD4 cells that expressed GzmB, perforin, and/or CD107a (29). These cells were found at significantly higher frequencies and exhibited greater cytotoxicity among patients with mild/moderate disease compared to those with severe or critical illness.…”

“…Herein, we review the characteristics of CD4 CTL across a range of human viral infections including human immunodeficiency virus type 1 (HIV-1) (9–11, 18–20), CMV (8, 10, 12, 21, 22), Epstein–Barr virus (EBV) (23–25), influenza (26, 27), viral hepatitis (28), hantavirus (29), dengue (30–33), and parvovirus B19 (34). CD4 CTL may also be involved more broadly in the regulation of immune responses, through regulatory T cell (Treg) function (to be discussed later) and may also be involved in other non-viral infections and anti-tumor responses.…”

Screening and Identification of an H-2Kb-Restricted CTL Epitope within the Glycoprotein of Hantaan Virus

“…Therefore, epitopes of HTNV NP that elicit CD4 + and CD8 + cytotoxic T lymphocyte responses have been extensively studied (Ennis et al, 1997; Van Epps et al, 1999; Lee et al, 2002). Viral GP-specific T cell responses have also been discovered (Ma et al, 2015). Protective immunity elicited through infection with recombinant HTNV-glycoprotein in murine models has also been demonstrated (Yu et al, 2013).…”