Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans

Abstract

Rhinovirus (RV) is a major cause of common cold and an important trigger of acute episodes of chronic lung diseases. Antigenic variation across the numerous RV strains results in frequent infections and a lack of durable cross-protection. Since the nature of human CD4+ T cells that target RV is largely unknown, T-cell epitopes of RV capsid proteins were analyzed, and cognate T cells characterized in healthy subjects and those infected by intranasal challenge. Peptide epitopes of the RV-A16 capsid proteins VP1 and VP2 were identified by peptide/MHCII tetramer-guided epitope mapping (TGEM), validated by direct ex vivo enumeration, and interrogated using a variety of in silico methods. Among non-infected subjects, those circulating RV-A16-specific CD4+ T cells detected at the highest frequencies targeted 10 unique epitopes that bound to diverse HLA-DR molecules. T-cell epitopes localized to conserved molecular regions of biological significance to the virus, were enriched for HLA class I and II binding motifs, and constituted both species-specific (RV-A) and pan-species (RV-A, -B and -C) varieties. Circulating epitope-specific T cells comprised both memory Th1 and T follicular helper cells, and were rapidly expanded and activated after intranasal challenge with RV-A16. Cross-reactivity was evidenced by identification of a common *0401-restricted epitope for RV-A16 and RV-A39 by TGEM, and the ability for RV-A16-specific Th1 cells to proliferate in response to their RV-A39 peptide counterpart. The preferential persistence of high-frequency RV-specific memory Th1 cells that recognize a limited set of conserved epitopes likely arises from iterative priming by previous exposures to different RV strains.

Immune Responses in Rhinovirus-Induced Asthma Exacerbations

“…As such, the T cell response must occur through activation of preexisting effector/memory T cells responding to common epitope(s) displayed by the infecting RV. Consistent with this, epitope mapping of RV targeting T cells had identified an HLA-DR4-restricted CD4-specific epitope of RV39 VP1 maps to a region that is conserved across RV groups A, B, and C [68••]. …”

Pathogenic CD4 + T cells in patients with asthma

“…Thus, studying this phenomenon could yield insight into the pathogenicity of T H 1 cells in asthmatic patients. After experimental infection of healthy subjects with HRV-A16, circulating HRV-specific CD4 + T cells identified by means of tetramer staining that expanded after infection were predominantly IFN-γ + 142 . Moreover, IFN-γ + CD4 + T cells are readily detected in BAL fluid from allergic asthmatic patients experimentally infected with HRV.…”

Respiratory virus-induced heterologous immunity

“…Since there are over 160 distinct RV strains characterized to date [9], reinfection with other strains is common. Viral capsid proteins (VP) of RV contain sequences [79] and T cell epitopes [80], which are conserved across strains. erefore, humoral or cellular cross-reactivity might provide cross-strain protection against heterologous RV infection.…”

“…Co culture of DCs, RV-A39 and T cells resulted in proliferation of CD4 + and CD8 + T cells and enhanced IFNγ production. Muehling et al [80] showed that pre-existing CD4 + Tm cells, speci c to conserved epitopes of the VP region, proliferate upon RV-A16 challenge in seronegative donors. CD4 + T m cells mainly showed a 1 or T follicular helper phenotype.…”

“…A larger cohort study with 175 HIV seropositive HLA-A2 + subjects con rmed HIV-1 and IV cross-reactivity. T cells of HIV + individuals frequently targeted the p17 GAG [77][78][79][80][81][82][83][84][85] and the IV-M1 58 epitopes in vitro [51]. About 40 % showed T cells speci c for both epitopes in vitro [51].…”