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

Foreman, Taylor W.; Nelson, Christine E.; Kauffman, Keith D.; Lora, Nickiana E.; Vinhaes, Caian L.; Dorosky, Danielle E.; Sakai, Shunsuke; Gómez, Felipe; Fleegle, Joel D.; Parham, Melanie; Perera, Shehan; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro; Brenchley, Jason M.; Queiroz, Artur T. L.; Andrade, Bruno B.; Kabát, Juraj; Via, Laura E.; Barber, Daniel L.

doi:10.1016/j.celrep.2022.110896

Cited by 23 publications

(19 citation statements)

References 54 publications

(55 reference statements)

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“…Thus, HIV appears to reduce the number of Mtb -specific T cells as well as the antimicrobial functionality of both CD4+ and CD8+ Mtb -specific T cells functionality. Foreman et al., 2022 ( 35 ), demonstrated in a rhesus macaque model that Mtb -specific CD4+ T cells are specifically decimated in granulomas from Mtb -SIV coinfected animals long before depletion is detectable in blood and that coinfection significantly decreased CD4+ T cell movement in granulomas ( 35 ).…”

Section: Mtb -Hiv Interactions In Pre-existing Tb Infectionmentioning

confidence: 99%

“…The discrepancy between these two studies in terms of the impact of coinfection on CCR5 positive cells, could be due to the time frame of the infections: CCR5 cells might increase in the period after coinfection but might be preferentially depleted as time goes on. Foreman et al., 2022 ( 35 ), demonstrated that SIV coinfected NHP granulomas had reduced frequency of CCR5-expressing Th1 and Th1* cells 2 weeks after SIV coinfection ( 35 ). Taken together, the cellular phenotype present in the Mtb granuloma likely provides an abundance of cells targeted by HIV in various stages of HIV progression.…”

Section: Mtb -Hiv Interactions In Pre-existing Tb Infectionmentioning

confidence: 99%

“…One major mechanism relates to the HIV-associated loss of macrophages and CD4+ T cells, both of which are instrumental in containing Mtb growth in granulomas ( 33 ). Since the hallmark of HIV infection is the slow depletion of CD4+ T cells over time, it has been suggested that CD4+ T cells in the granulomas of Mtb infected patients could provide a large source of target cells for HIV infection, and that their depletion directly interferes with granuloma control ( 34 , 35 ). Foreman et al., 2022 ( 35 ) has demonstrated that CD4+ T cells within granulomas are directly depleted within 2 weeks following SIV coinfection of NHPs with LTBI before any detectable changes in CD4+ T cell counts in peripheral locations.…”

Section: Introductionmentioning

confidence: 99%

“…Since the hallmark of HIV infection is the slow depletion of CD4+ T cells over time, it has been suggested that CD4+ T cells in the granulomas of Mtb infected patients could provide a large source of target cells for HIV infection, and that their depletion directly interferes with granuloma control ( 34 , 35 ). Foreman et al., 2022 ( 35 ) has demonstrated that CD4+ T cells within granulomas are directly depleted within 2 weeks following SIV coinfection of NHPs with LTBI before any detectable changes in CD4+ T cell counts in peripheral locations. This directly supports evidence that HIV-infected individuals have shown a 2- to 3- fold increase in the transition to active TB within the first year of HIV coinfection when CD4+ T cells are still relatively abundant ( 36 ).…”

Section: Introductionmentioning

confidence: 99%

“…Mechanisms in addition to CD4+ T cell depletion that have been implicated in the synergistic interactions between Mtb and HIV include: disruption of the pro- and anti-inflammatory cytokine balance, impairment of CD4+ T cell and Mtb -specific T cell functionality, Mtb -induced increase in HIV viral load, viral evolution within granulomas, chronic immune activation, and HIV impairment of innate immune cells ( 23 – 26 , 28 , 30 , 32 , 35 , 39 , 40 ). However, the role and relative impact of all of these mechanisms within Mtb granulomas remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Systems biology approaches to investigate the role of granulomas in TB-HIV coinfection

Hoerter

Arnett²,

Schlesinger³

et al. 2022

Front. Immunol.

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The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy between Mycobacterium tuberculosis (Mtb) and HIV during coinfection include: disruption of cytokine balances, impairment of innate and adaptive immune cell functionality, and Mtb-induced increase in HIV viral loads. Tuberculosis granulomas are the interface of host-pathogen interactions. Thus, granuloma-based research elucidating the role and relative impact of coinfection mechanisms within Mtb granulomas could inform cohesive treatments that target both pathogens simultaneously. We review known interactions between Mtb and HIV, and discuss how the structure, function and development of the granuloma microenvironment create a positive feedback loop favoring pathogen expansion and interaction. We also identify key outstanding questions and highlight how coupling computational modeling with in vitro and in vivo efforts could accelerate Mtb-HIV coinfection discoveries.

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Section: Mtb -Hiv Interactions In Pre-existing Tb Infectionmentioning

confidence: 99%

Section: Mtb -Hiv Interactions In Pre-existing Tb Infectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Systems biology approaches to investigate the role of granulomas in TB-HIV coinfection

Hoerter

Arnett²,

Schlesinger³

et al. 2022

Front. Immunol.

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The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

da Silva Antunes,

Weiskopf,

Sidney

et al. 2023

Current Protocols

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Epitopes recognized by T cells are a collection of short peptide fragments derived from specific antigens or proteins. Immunological research to study T cell responses is hindered by the extreme degree of heterogeneity of epitope targets, which are usually derived from multiple antigens; within a given antigen, hundreds of different T cell epitopes can be recognized, differing from one individual to the next because T cell epitope recognition is restricted by the epitopes’ ability to bind to MHC molecules, which are extremely polymorphic in different individuals. Testing large pools encompassing hundreds of peptides is technically challenging because of logistical considerations regarding solvent‐induced toxicity. To address this issue, we developed the MegaPool (MP) approach based on sequential lyophilization of large numbers of peptides that can be used in a variety of assays to measure T cell responses, including ELISPOT, intracellular cytokine staining, and activation‐induced marker assays, and that has been validated in the study of infectious diseases, allergies, and autoimmunity. Here, we describe the procedures for generating and testing MPs, starting with peptide synthesis and lyophilization, as well as a step‐by‐step guide and recommendations for their handling and experimental usage. Overall, the MP approach is a powerful strategy for studying T cell responses and understanding the immune system's role in health and disease. © 2023 Wiley Periodicals LLC.Basic Protocol 1: Generation of peptide pools (“MegaPools”)Basic Protocol 2: MegaPool testing and quantitation of antigen‐specific T cell responses

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