CD4⁺T-Cell Reconstitution Reduces Cytomegalovirus in the Immunocompromised Brain

Abstract

Cytomegalovirus (CMV) infection is the most common opportunistic infection of the central nervous systemin patients with human immunodeficiency virus or AIDS or on immunosuppressive drug therapy. Despite medical management, infection may be refractory to treatment and continues to cause significant morbidity and mortality. We investigated adoptive transfer as an approach to treat and prevent neurotropic CMV infection in an adult immunodeficient mouse model. SCID mice were challenged with intracranial murine CMV (MCMV) and reconstituted with MCMV-or vesicular stomatitis virus (VSV)-sensitized splenocytes, T cells, or T-cell subsets. T cells labeled with vital dye or that constitutively generated green fluorescent protein (GFP) were identified in the brain as early as 3 days following peripheral transfer. Regardless of specificity, activated T cells localized to regions of the brain containing CMV, however, only those specific for CMV were effective at clearing virus. Reconstitution with unsorted MCMV-immune splenocytes, enriched T-cell fractions, or CD4؉ cells significantly reduced virus levels in the brain within 7 days and also prevented clinical disease, in significant contrast with mice given VSV-immune unsorted splenocytes, MCMV-immune CD8 ؉ T cells, and SCID control mice. Results suggest CMV-immune T cells (particularly CD4 ؉ ) rapidly cross the blood-brain barrier, congregate at sites of specific CMV infection, and functionally eliminate acute CMV within the brain. In addition, when CMV-immune splenocytes were administered prior to a peripheral CMV challenge, CMV entry into the immunocompromised brain was prevented. Systemic adoptive transfer may be a rapid and effective approach to preventing CMV entrance into the brain and for reducing neurotropic infection.

Cytomegalovirus infection and interferon-γ modulate major histocompatibility complex class I expression on neural stem cells

“…A similar study reported that murine CMV-specific immune cells, particularly CD4+ T-cells, rapidly cross the blood-brain barrier, congregate at sites of specific MCMV infection, and eliminate acute MCMV within the brain (Reuter et al , 2005). These studies suggest that infiltrating T-cells clear viral brain infection potentially through an MHC dependent, perforin-mediated cytotoxic T lymphocyte (CTL) response.…”

Cytomegalovirus InducesInterferon-Stimulated Gene Expression and Is Attenuated by Interferon in the DevelopingBrain

“…The adult brain is protected from CMV by a number of mechanisms, including a CD4 (39) and peripheral CD8 (36) T-cell response. We have previously shown that developing brain cells in vivo and in vitro are more likely to show mCMV infections than mature brain cells, and that this preference is independent of the host B-and T-cell responses (57,61).…”

The CD4+ T Cell Response to Human Cytomegalovirus in Healthy and Immunocompromised People

“…Later studies using the same murine system also demonstrated that controlling CMV mediated lung disease in treated mice required CD8+ T cells rather than CD4+ T cells (Steffens et al, 1998;Podlech et al, 2000). However, when adoptive transfer was performed in severe combined immunodeficiency (SCID) mice, CD4+ T cells were able to prevent viral dissemination in the brain (Reuter et al, 2005). Overall, therefore, CD4+ T cells appear to be essential only for control of viral replication in the specific organs in the mouse model.…”