Immune Regulation in Mycobacterial and Fungal Infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Human immunodeficiency virus (HIV) infection gradually depletes circulating CD4 T cells leading to the development of acquired immunodeficiency syndrome (AIDS) and impaired host resistance to microbial infections. CD4 T cells are essential for control of Mycobacterium tuberculosis (Mtb) infection, and tuberculosis (TB) is the leading cause of death in persons living with HIV (PLWH). The extent of peripheral CD4 T cell depletion in PLWH correlates with increasing risk of developing active TB. However, there is also an increased incidence of active TB in PLWH that have normal-to-high CD4 T cell counts in blood. The elevated risk of TB in individuals with normal CD4 T cell counts is incompletely understood, but may reflect detrimental impact of antiviral inflammation (e.g. type I interferons) on anti-mycobacterial innate immunity, impairment of macrophage function, or preferential depletion of CD4 T cells in tissues compared to circulation. Mtb persists in granulomas, complex structures comprised of multiple immune cell types which reproducibly position themselves relative to one another. Although variable by many respects, granulomas can be generally described by a few key features including: an oft-necrotic, macrophage-rich, core where mycobacteria are primarily located, a lymphocyte-rich cuff circumscribing the macrophage core, and B cell-rich tertiary lymphoid substructures referred to as Granuloma-Associated Lymphoid Tissue (GrALT) located within the lymphocyte cuff or found as proximal granuloma satellites. CD4 T cells are primarily found in the lymphocyte cuff but can also be seen interacting with macrophages in the core or with B cells in GrALT. Due to the difficulty of studying human lung infections, little is understood about the effects of HIV infection on Mtb granulomas. Previous studies have shown that SIV infection of macaques recapitulates the gradual loss of circulating CD4 T cells and eventual development of active tuberculosis disease as seen in humans. In this reporting period, we examined the very early effects of SIV infection on CD4 T cell responses at the site of Mtb infection in rhesus macaques to ask if CD4 T cells within the granuloma microenvironment are differentially susceptible to dysfunction and depletion during SIV infection as compared to T cells in circulation or lymphoid tissues. We found that CD4 T cells are lost from Mtb granulomas much faster than previously thought. In only two weeks after SIV infection, CD4 T cells are largely depleted from granulomas, long before any evidence of peripheral T cell loss. Mtb-specific CD4 T cells, and in particular those expressing CCR5, were preferentially lost over non-specific T cells. Moreover, using live imaging analysis of thick section granuloma explants, we show that the few T cells that are left are unable to move about inside of the granuloma. Thus, HIV infection may result in a dramatic loss of T cells from Mtb granulomas before the individual even experiences the first symptoms of acute HIV infection.