Initial capsid‐specific CD4⁺ T cell responses protect against Theiler's murine encephalomyelitisvirus‐induced demyelinating disease

Abstract

Central nervous system (CNS) infection by Theiler's murine encephalomyelitis virus (TMEV) causes an immune‐mediated demyelinating disease similar to human multiple sclerosis in susceptible mice. To understand the pathogenic mechanisms, we analyzed the level, specificity, and function of CD4+ Th cells in susceptible SJL/J and resistant C57BL/6 mice. Compared to resistant mice, susceptible mice have three‐ to fourfold higher levels of overall CNS‐infiltrating CD4+ T cells during acute infection. CD4+ T cells in the CNS of both strains display various activation markers and produce high levels of IFN‐γ upon stimulation with anti‐CD3 antibody. However, susceptible mice display significantly fewer (tenfold) IFN‐γ‐producing Th1 cells specific for viral capsid epitopes as compared to resistant mice. Furthermore, preimmunization with capsid‐epitope peptides significantly increased capsid‐specific CD4+ T cells in the CNS during the early stages of viral infection and delayed the development of demyelinating disease in SJL/J mice. This suggests a protective role of capsid‐reactive Th cells during early viral infection. Therefore, a low level of the protective Th1 response to viral capsid proteins, in conjunction with Th1 responses to unknown epitopes may delay viral clearance in susceptible mice leading to pathogenesis of demyelination during acute infection, as compared to resistant mice.

Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice

“…The importance of CD8 ϩ T cells in viral resolution is consistent with previous reports of mice with resistant backgrounds (38,45,47). However, it is also possible that deficiencies in virus-specific CD4 ϩ T-cell and antibody responses in P1-Tg mice contribute to the lack of viral clearance, as these immune responses play a role in TMEV clearance from the CNS, especially during the early stages of viral infection (6,22,40,43). Surprisingly, however, TMEV-infected B6 P1-Tg mice with high levels of viral persistence developed neither symptomatic disease nor demyelinating lesions as late as 250 days pi (Fig.…”

“…Moreover, when FVB/D b -transgenic (Tg) mice were tolerized by a soluble VP2 121-130 peptide infusion, their susceptibility was reinstated; these mice exhibited extensive demyelination and high viral loads (38). Like the CD8 ϩ T cells, vigorous antiviral CD4 ϩ T-cell responses in the early stages of viral infection also are important in acquiring resistance to TMEV-IDD (40). Furthermore, virus-specific antibody responses are required to confer resistance to TMEV infection, especially in the absence of CD8 ϩ T cells (22).…”

Multifunctional CD4 Cells Expressing Gamma Interferon and Perforin Mediate Protection against Lethal Influenza Virus Infection

“…The physiological role of cytolytic CD4 cells has thus far not been elucidated; however, in many infections, CD4 cells have been shown to contribute to viral clearance (5,22,24,25). Certainly, during influenza virus infection, in vitro-generated CD4 CTLs and memory CD4 cells have been shown to lower viral titers (7, 40; McKinstry et al, submitted).…”

Differential Virus Replication, Cytokine Production, and Antigen-Presenting Function by Microglia from Susceptible and Resistant Mice Infected with Theiler's Virus

“…A number of CD4 ϩ T cells specific for TMEV during the course of disease in SJL mice recognize four predominant viral capsid epitopes (VP1 233-250 , VP2 74-86 , VP3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37] , and VP4 [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] ), with one each on the external and internal capsid proteins (10,19,55,56). The external capsid epitopes appear to account for the majority (ϳ80%) of major histocompatibility complex (MHC) class II-restricted T-cell responses to TMEV capsid proteins (55,57).…”

“…Recently, viral capsid epitopes recognized by CNS-infiltrating CD4 ϩ T cells from TMEV-infected B6 mice have also been identified (18). When levels of virus capsid-specific CD4 ϩ T cells in the CNS are compared between B6 and SJL mice at early stages of viral infection, significantly higher levels are found in the CNS of resistant B6 mice (30), suggesting that virus-specific CD4 ϩ T cells are important for protection from demyelinating disease during initial immune responses (2). Similarly, levels of CNSinfiltrating virus-specific CD8 ϩ T cells in the CNS are as much as threefold higher in resistant mice at the same time point (28).…”