Role and specificity of regulatory T cells during retroviral infection.
Doctoral thesis, UCL (University College London).
During chronic viral infection of the hematopoietic system, both virus-mediated and immune-mediated effects may cause bone marrow dysfunction leading to cytopenias. To study the pathological consequences of the T helper response to unresolving chronic infection, a system was developed using infection of immunodeficient mice with Friend virus (FV). FV is a murine retroviral complex, which causes non-cytopathic persistent infection of hematopoietic cells. The results obtained suggested that unregulated CD4+ T cell response to FV causes bone marrow pathology and anaemia. Regulatory T (Treg) cells are a subset of CD4+ T cells which have been shown to suppress immune responses and to have protective roles in other models of bone marrow pathology. Therefore, the role of Treg cells in the model of FV-induced immune pathology was addressed. Bone marrow pathology was triggered by local gamma interferon (IFN-γ) production by FV-specific CD4+ T cells and was associated with relative low numbers of Treg cells, while enrichment of the Treg cell population protected against development of the immune pathology, by suppressing IFN-γ production by pathogenic CD4+ T cells. The specificity of Treg cells is still a matter of controversy, with studies suggesting they are mainly self-reactive while other studies indicate they can be reactive to foreign antigens. The issue of Treg cell specificity was addressed in the FV-induced immune pathology model. Analysis of mice transgenically expressing the TCRβ chain of a FVspecific CD4+ T cell clone, which harbor a polyclonal TCR repertoire with increased frequency of FV-specific CD4+ T cells, indicated that the TCR repertoire of Treg cells in virus-naïve mice was virtually devoid of FV-specific clones. Moreover, FV infection did not cause expansion of a small number of virus-specific Treg cells or conversion of virusspecific effector T cells into Forkhead box P3 (FoxP3)-expressing Treg cells. Importantly, pathogenic CD4+ T cells and Treg cells differed dramatically in their requirements for direct recognition of viral antigens, since bone marrow pathology driven by FV-specific TCRβ-transgenic CD4+ T cells was efficiently suppressed by virusnonspecific Treg cells. Therefore, protection from bone marrow pathology in chronic viral infections may be provided by sufficient numbers of polyclonal Treg cells.
|Title:||Role and specificity of regulatory T cells during retroviral infection|
|Open access status:||An open access version is available from UCL Discovery|
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