T follicular helper cells differentiate from Th2 cells in response to helminth antigens

The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4+ T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4–producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5− PD-1− IL-4/GFP+ CD4+ T cells after their transfer into naive mice and antigen challenge in vivo

The development and maintenance of B cell responses to microbial challenge

Humoral responses are a critical component of the immune system and antibodies play an important role in the response to many pathogens. The work presented in this thesis examines the development, maintenance, and regulation of antibody production. T follicular helper (TFH) cells have been shown to provide B cell help in germinal centers (GCs). However, infection with T. gondii results in a loss of splenic organization, including the GCs. Thus, studies were performed to evaluate this splenic disorganization and the effects of this process on antibody responses. Furthermore, experiments to better understand the development of TFH cells revealed that TFH cells can arise from CD4+ T cells that have committed to the Th2 lineage in response to SEA immunization. However, aberrant B cell response can lead to antibody-mediated autoimmune disease, thus studies were conducted to further elucidate regulatory mechanisms to control GC responses. These revealed that IL-27 can inhibit GC responses through effects on TFH cells and directly through B cells. Finally, antibody responses are maintained long term through long-lived plasma cells in the bone marrow. Analysis of the Treg population in the bone marrow demonstrates a role for these cells in maintaining plasma cells, a relationship that can be transiently disrupted as both populations are lost during infection. Collectively, these studies highlight developmental processes and regulatory mechanisms that support B cell responses

The development and maintenance of B cell responses to microbial challenge

Humoral responses are a critical component of the immune system and antibodies play an important role in the response to many pathogens. The work presented in this thesis examines the development, maintenance, and regulation of antibody production. T follicular helper (TFH) cells have been shown to provide B cell help in germinal centers (GCs). However, infection with T. gondii results in a loss of splenic organization, including the GCs. Thus, studies were performed to evaluate this splenic disorganization and the effects of this process on antibody responses. Furthermore, experiments to better understand the development of TFH cells revealed that TFH cells can arise from CD4+ T cells that have committed to the Th2 lineage in response to SEA immunization. However, aberrant B cell response can lead to antibody-mediated autoimmune disease, thus studies were conducted to further elucidate regulatory mechanisms to control GC responses. These revealed that IL-27 can inhibit GC responses through effects on TFH cells and directly through B cells. Finally, antibody responses are maintained long term through long-lived plasma cells in the bone marrow. Analysis of the Treg population in the bone marrow demonstrates a role for these cells in maintaining plasma cells, a relationship that can be transiently disrupted as both populations are lost during infection. Collectively, these studies highlight developmental processes and regulatory mechanisms that support B cell responses

Infection-elicited microbiota promotes host adaptation to nutrient restriction.

The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent

T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow

Long-lived plasma cells (PCs) in the bone marrow (BM) are a critical source of antibodies after infection or vaccination, but questions remain about the factors that control PCs. We found that systemic infection alters the BM, greatly reducing PCs and regulatory T (Treg) cells, a population that contributes to immune privilege in the BM. The use of intravital imaging revealed that BM Treg cells display a distinct behavior characterized by sustained co-localization with PCs and CD11c-YFP+ cells. Gene expression profiling indicated that BM Treg cells express high levels of Treg effector molecules, and CTLA-4 deletion in these cells resulted in elevated PCs. Furthermore, preservation of Treg cells during systemic infection prevents PC loss, while Treg cell depletion in uninfected mice reduced PC populations. These studies suggest a role for Treg cells in PC biology and provide a potential target for the modulation of PCs during vaccine-induced humoral responses or autoimmunity