CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

Abstract

The HIV-mediated decline in circulating CD4 T cells correlates with increased risk of active tuberculosis (TB). However, HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals also have an increased incidence of TB prior to loss of CD4 T cells in blood, raising the possibility that HIV co-infection leads to disruption of CD4 T cell responses at the site of lung infection before they are observed systemically. Here we used a rhesus macaque model of SIV/Mtb co-infection to study the early effects of acute SIV infection on CD4 T cells in pulmonary Mtb granulomas. Two weeks after SIV co-infection CD4 T cells were dramatically depleted from granulomas, before significant bacterial outgrowth, disease reactivation as measured by PET-CT imaging, or CD4 T cell loss in blood, airways, and lymph nodes. Mtb-specific CD4 T cells, CCR5-expressing, in granulomas were preferentially depleted by SIV infection. Moreover, CD4 T cells were preferentially depleted from the granuloma core and lymphocyte cuff relative to B cell-rich regions, and live imaging of granuloma explants showed that SIV co-infection reduced T cell motility. Thus, Mtb-specific CD4 T cells in pulmonary granulomas may be decimated before many patients even experience the first symptoms of acute HIV infection.

High-parameter phenotypic characterization reveals a subset of human Th17 cells that preferentially produce IL17 againstM. tuberculosisantigen

“…To study the effects of LTBI and ART-treated HIV (HIV-ART) on Th17 cells defined by different criteria, we designed a spectral flow cytometry panel encompassing cytokines, chemokine receptors, transcription factors and cell surface markers (Figure 1A&C). We used the following nomenclature: (a) T H 17 are CD26 + CD161 + [18,19]; (b) T17 are CCR6 + CXCR3 - [14,17]; and (c) T1T17 are CCR6 + CXCR3 + [17,31]. We first gated out Vα7.2 + CD4 + T cells to exclude MAIT cells that share certain markers with Th17 cells [32], since MAITs can produce IL17 [33].…”

Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques

“…It is possible that the elevated expression of CCR5 on CD4 T cells in airways combined with Mtb coinfection created a target-rich environment for SIV, thereby resulting in their selective depletion (22). Interestingly, others have shown that CCR5+ CD4+ T cells are rapidly depleted in granulomas from untreated Mtb/SIV coinfected macaques (82). These data suggest that ART may have prevented depletion of CCR5+ CD4+ T cells in granulomas of our SIV-infected macaques.…”

Mycobacterium tuberculosisdisease associates with higher HIV-1-specific antibody responses

“…During Mtb disease and chronic HIV-1 infection, both microorganisms can be found in lymph nodes, which are the primary site for B cell development and antibody production. Furthermore, both organisms may be present in granulomas formed during Mtb disease (22, 23), and granulomas are often classified as secondary lymphoid structures (69, 70). Mtb is known to engage pathogen recognition receptors (PRR), such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein 2 ( NOD2), and these are present on the lymphoid tissue-resident follicular dendritic cells (FDCs), CD4+ T follicular helper (TFH), and B cells (71).…”

“…For instance, increased interleukin (IL)-6 observed in PWH and Mtb disease can drive the secretion of IL-21 in naïve and memory T cells to promote antibody production (21). Mycobacteria and HIV-1 can also co-exist in the same anatomic region, such as lymph nodes, and even in the same cell, such as macrophages (16,22,23), and this co-localization may also impact the subsequent immune response. Based on CFA’s known actions, unique Mtb-induced inflammation, and Mtb-HIV-1 co-localization, we hypothesized that Mtb disease may augment humoral immune responses against HIV-1.…”