Regulatory T cells (Treg) play critical roles in the modulation of immune responses to infectious agents. Further understanding of the factors that control Treg activation and expansion in response to pathogens is needed to manipulate Treg function in acute and chronic infections. Here we show that chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus results in a marked expansion of Foxp3 + Treg that is dependent on retroviral superantigen (sag) genes encoded in the mouse genome. Sagdependent Treg expansion was MHC class II dependent, CD4 independent, and required dendritic cells. Thus, one unique mechanism by which certain infectious agents evade host immune responses may be mediated by endogenous Sag-dependent activation and expansion of Treg.

The production of antibody-secreting plasma cells and memory B cells requires the interaction of T follicular helper (Tfh) cells with B cells in the follicle and is modulated by T follicular regulatory (Tfr) cells. We compare the effects of Tfr cells in an in vitro model of bystander Tfh function in the absence of BCR engagement and in a model in which mimics cognate T-B interactions in which the BCR is engaged. In the absence of Tfr cells, Tfh cells from primed mice induce naive B cell differentiation into GC B cells and class switch recombination (CSR) in the presence of anti-CD3 alone or anti-CD3/IgM in a contact-dependent manner. Addition of primed Tfr cells efficiently suppressed GC B cell proliferation, differentiation and CSR in the anti-CD3 alone cultures, but only moderately suppressed BCR-stimulated B cells. When stimulated with anti-CD3 alone, IL-4 is critical for the induction of GC B cells and CSR. IL-21 plays a minimal role in GC B cell differentiation, but a greater role in switching. When the BCR is engaged, IL-4 is primarily required for switching and IL-21 only modestly affects switching. CD40L expression was critical for Tfh-mediated B cell proliferation/differentiation in the absence of B cell engagement. When the BCR was engaged, proliferation of CD40 deficient B cells was partially restored, but was susceptible to suppression by Tfr. These studies suggest that in vitro Tfr suppressor function is complex and is modulated by BCR signaling and CD40-CD40L interactions.

Mounting evidence has demonstrated the presence of a population of thymic CD8+ T cells that share phenotypic and functional similarity to “innate-like” or “memory-like” T cells. Innate CD8+ T cells have increased expression of CD44, CD122, and Eomesodermin (Eomes), as well as the capacity to rapidly produce interferon (IFN)-γ upon stimulation. In addition to several gene-deficient models, including KLF2-, Itk-, and Id3-deficient mice, innate CD8+ T cells have also been documented in naïve BALB/c mice. The development of such cells is dependent on the production of interleukin (IL)-4 from an expanded population of αβ or γδ NKT cells expressing the transcription factor promyelocytic leukemia zinc finger (PLZF). Interestingly, this innate phenotype among CD8+ T cells is lost in congenic BALB/c mice lacking all endogenous mouse mammary tumor proviruses (BALB/Mtv-null). In the absence of endogenous Mtv proviruses, the expression of CD44, CD122, CXCR3, and Eomes, as well as the production of IFN-γ, was greatly reduced among thymic CD8+ T cells. The loss of this innate CD8+ T cell population in BALB/Mtv-null mice correlated with a reduction in PLZF+, IL-4 secreting αβ NKT cells within the thymus compared to wild type BALB/c. Our findings suggest a potential Mtv-mediated role in modulation of thymic αβ NKT cell development that subsequently influences the generation of innate CD8+ T cells.