Glenn K. Matsushima

Studies on the mechanism of protection from acute viral encephalomyelitis by delayed-type hypersensitivity inducer T cell clones

Abstract Previous studies have shown that mice can be protected from a lethal infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) by the adoptive transfer of delayed-type hypersensitivity (DTH)-inducer T cell clones specific for the virus. Protection does not involve the suppression of virus replication in the central nervous system (CNS) or via augmentation of the antiviral antibody response. In the present report we have compared the CNS lesions induced by JHMV in lethally infected and T cell clone protected mice. The presence of virus-specific T cell clones induced a transient increase in mononuclear cell infiltration into the parenchyma of the brains of protected mice, consistent with previous data suggesting that a DTH response was responsible for protection. Immunohistochemical studies suggested further that virus was not replicating in the ependyma or cellular infiltrate, but that the presence of the T cell clone prevented neuronal infection. While the mechanism of effectively altering the in vivo cellular tropism is unknown, survival is accompanied by increased specific destruction of target tissues with fulminant CNS demyelination and an increased incidence of persistent infection.

Delayed-type hypersensitivity response in the central nervous system during JHM virus infection requires viral specificity for protection.

Abstract The JHM strain of mouse hepatitis virus (JHMV) elicits an I-A-restricted delayed-type hypersensitivity (DTH) response mediated by a Thy-1+, Lyt-1+, and CD4+ T cell. Adoptive transfer of these polyclonal CD4+ T cells from immunized mice prevents death in lethally infected recipients without significantly reducing virus titer in the central nervous system (CNS). These observations raise the possibility that the recruitment of mononuclear cells into the CNS may play a critical role in survival from a lethal CNS infection. Transient DTH response to nonviral antigens induced an accumulation of monocytes in the CNS that was maximal at 48 h post-challenge and virtually resolved by 5 days post-challenge. By contrast the induction of prolonged DTH responses resulted in the accumulation of a large number monocytes that persisted in the CNS for at least 5 days post-challenge. Neither type of DTH reaction suppressed virus replication or prevented death from concomitant lethal JHMV infection.

Evidence for a subpopulation of antigen-presenting cells specific for the induction of the delayed-type hypersensitivity response

Young adult SJL mice (8 weeks of age or younger) do not mount a delayed-type hypersensitivity (DTH) response due to the failure of a macrophage antigen-presenting cell (APC) to induce TDTH effector cells. SJL mice that are 10 weeks of age or older produce a normal DTH response. This genetic defect provides a model for the investigation of functional subpopulations of APC which interact with specific subpopulations of T cells. In this study, we used this model to examine whether macrophage APC impairment involves APC-dependent immune responses other than DTH. No age-dependent differences were found in the ability of spleen cells from SJL mice to proliferate and synthesize interleukin-2 in response to concanavalin A; nor was the proliferative response to a variety of antigenic stimuli affected. In addition, no differences were observed in the contact sensitivity response or in the in vitro generation of allogeneic cytotoxic T lymphocytes (CTL). In contrast, the in vivo generation of allogeneic CTL was significantly depressed in 6-week-old SJL and could not be restored to normal by the adoptive transfer of macrophages from DTH responsive 12-week-old SJL mice. Finally, examination of the humoral response of 6-week-old SJL indicated no impairment in IgM or IgG serum antibody levels or in the induction of splenic B cells. Thus, the macrophage APC regulating the induction of TDTH effector cells does not appear to participate in the induction of T helper cells for other cellular and humoral responses. These data support the hypothesis that distinct subpopulations of APC may regulate the induction of specific immune effector mechanisms.

Fine Specificity and Genetic Restriction of T Cell Clones Specific for Mouse Hepatitis Virus, Strain JHM

Mouse hepatitis viruses are members of the coronavirus group of animal viruses. Although named for their propensity to induce acute hepatitis in animals stressed by a variety of conditions, it has become clear that as a group they possess the ability to cause a diverse group of diseases in their natural host (Wege, et al, 1982). One strain of MHV, named JHM virus (JHMV), was isolated from mice found to have demyelinated lesions of the central nervous system (Bailey, et al, 1949). More recently it has been found that JHMV is not only capable of causing acute encephalomyelitis with demyelination but also chronic demyelination probably due to the establishment of a latent infection of oligodendroglia, the cells of myelin within the central nervous system (Herndon, et al, 1975; Stohlman and Weiner, 1981).