Dissecting Mycobacterium tuberculosis immune evasion of dendritic cell-T cell crosstalk Public
Enriquez, Ana Beatriz (Spring 2022)
Published
Abstract
Mycobacterium tuberculosis (Mtb), is the causative agent of tuberculosis (TB), an infectious disease that continues to cause a significant burden to public health worldwide. While the only licensed vaccine, BCG, is able to prevent disseminated disease in children, it is ineffective at preventing pulmonary TB. Current efforts to develop efficacious vaccines and adjuvants are hindered by a lack of understanding of the mechanisms that contribute to protective immune responses against TB. Moreover, we need to understand how to overcome Mtb evasion strategies in order to induce protective immunity through vaccination. Therefore, insights that address these critical gaps in knowledge are necessary to advance the development of efficacious TB vaccines and adjuvants.
Recent studies have identified a critical role for CD4+ T helper 17 (Th17) cells in protective immunity to TB. However, Th17 responses are limited during Mtb infection and the molecular signals that contribute to restricting these responses are poorly understood. Mtb limits Th17 responses during infection by impairing the functions of dendritic cells (DCs), which are important for presenting pathogen-derived antigens and for initiating T cell responses. Our laboratory has previously demonstrated that Mtb restricts Th17 polarization by impeding CD40 signaling on DCs, and that exogenous engagement of the CD40-CD40L pathway enhances Th17 polarization during Mtb infection. However, the molecular basis for CD40-dependent Th17 polarization remained unknown. We found that the canonical Notch ligand, DLL4, is upregulated downstream of CD40 signaling on DCs and is necessary for Th17 polarization. Exogenous CD40 engagement increased Dll4 mRNA and surface expression of DLL4 on Mtb-infected DCs. Blocking DLL4 impaired the ability of DCs to polarize Th17 responses in vitro and in vivo in mouse models of TB. Interestingly, DLL4 blockade also led to a significant reduction in the polarization of multi-functional Th17 responses. We then elucidated the mechanism by which Mtb impedes these responses and found that the Mtb Hip1 serine protease limits DLL4 expression by impairing CD40 signaling on DCs.
Having demonstrated that engaging CD40 augments protective immune responses during infection, we then used RNA sequencing to elucidate additional transcriptional mechanisms downstream of CD40 on DCs that contribute to enhanced T cell functions. We found that engaging CD40 on Mtb-infected DCs led to reprogramming of the DC transcriptome, including significant increases in the ability of DCs to secrete Th1- and Th17-polarizing cytokines and DC migration-inducing chemokines, and upregulation of co-stimulatory molecules. Moreover, we found that exogenously engaging CD40 on DCs led to a significant increase in the capacity of T cells to proliferate, and that blocking key co-stimulatory molecules led to a significant decrease in proliferation.
Collectively, these insights address critical gaps in knowledge by elucidating the molecular mechanisms that dictate polarization of protective T cell responses during Mtb infection. Moreover, we have demonstrated how Mtb is able to evade host immunity by impairing DC-T cell crosstalk and have shown that engaging CD40 is able to overcome pathogen evasion to induce critical DC functions. The insights generated here will contribute to the development of more efficacious TB vaccines and adjuvants for TB.
Table of Contents
CHAPTER I
Introduction......................................................................................1
CHAPTER II
Mycobacterium tuberculosis impedes CD40-dependent Notch signaling
to restrict Th17 polarization during infection......................................32
CHAPTER III
Engaging CD40 enhances dendritic cell functions that augment T cell
responses during Mycobacterium tuberculosis infection .....................97
CHAPTER IV
Discussion.....................................................................................134
CHAPTER V
Bibliography..................................................................................145
APPENDIX
Unpublished data and published manuscripts..................................186
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