Diversity in the T cell response to Chlamydia-sum are better than one

Labuda, Jasmine C.; McSorley, Stephen J.

doi:10.1016/j.imlet.2018.08.002

Cited by 16 publications

(14 citation statements)

References 70 publications

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“…After infection, naïve CD4 T cells mature into Th1, Th2, Th17, Tfh, or Treg lineages that can help or impede other immune cells to kill microbes. In the case of Chlamydia infection, it is widely believed that CD4 Th1 cells are the major effector lineage that orchestrates bacterial clearance from the reproductive tract [10,11,[21][22][23]. Th1 cells are often required to coordinate the immune response against intracellular pathogens via their capacity to activate macrophages through secretion of IFN-γ [24].…”

Section: Introductionmentioning

confidence: 99%

Th1 cells are dispensable for primary clearance of Chlamydia from the female reproductive tract of mice

2022

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Protective immune responses to Chlamydia infection within the female reproductive tract (FRT) are incompletely understood. MHC class II-restricted CD4 Th1 responses are believed to be vital for bacterial clearance due to their capacity to secrete IFN-γ, but an essential requirement for T-bet-expressing Th1 cells has yet to be demonstrated in the mouse model of Chlamydia infection. Here, we investigated the role of T-bet and IFN-γ in primary clearance of Chlamydia after FRT infection. Surprisingly, IFN-γ producing CD4 T cells from the FRT expressed low levels of T-bet throughout infection, suggesting that classical T-bet-expressing Th1 cells are inefficiently generated and therefore unlikely to participate in bacteria clearance. Furthermore, mice deficient in T-bet expression or with a CD4-specific T-bet deficiency cleared FRT infection similarly to wild-type controls. T-bet-deficient mice displayed significant skewing of FRT CD4 T cells towards Th17 responses, demonstrating that compensatory effector pathways are generated in the absence of Th1 cells. In marked contrast, IFN-γ-, and IFN-γR-deficient mice were able to reduce FRT bacterial burdens, but suffered systemic bacterial dissemination and 100% mortality. Together, these data demonstrate that IFN-γ signaling is essential to protect mice from fatal systemic disease, but that classical T-bet-expressing Th1 cells are non-essential for primary clearance within the FRT. Exploring the protective contribution of Th1 cells versus other CD4 effector lineages could provide important information for the generation of new Chlamydia vaccines.

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Section: Introductionmentioning

confidence: 99%

Th1 cells are dispensable for primary clearance of Chlamydia from the female reproductive tract of mice

2022

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“…For Chlamydia, infection is largely restricted to epithelial cells at barrier tissues such as the eyes, lungs and the reproductive tract. As such, it is reasonable to speculate that protective immunity to Chlamydia would be more complex than Th1-dependent IFN production (9). The mouse models of Chlamydia female reproductive tract infection provide an invaluable tool for studying host immunity to Chlamydia infection.…”

Section: Introductionmentioning

confidence: 99%

Innate IFN-γ Is Essential for Systemic Chlamydia muridarum Control in Mice, While CD4 T Cell-Dependent IFN-γ Production Is Highly Redundant in the Female Reproductive Tract

Mercado

Malaviarachchi

et al. 2021

Infect Immun

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Protective immunity against the obligate intracellular bacterium Chlamydia has long been thought to rely on CD4 T cell-dependent IFNγ production. Nevertheless, whether IFNγ is produced by other cellular sources during Chlamydia infection and how CD4 T cell-dependent and -independent IFNγ contribute differently to host resistance has not been carefully evaluated. In this study, we dissect the requirements of IFNγ produced by innate immune cells and CD4 T cells for resolution of Chlamydia muridarum female reproductive tract (FRT) infection. After C. muridarum intravaginal infection, IFNγ-deficient and T cell-deficient mice exhibited opposite phenotypes for survival and bacterial shedding at the FRT mucosa, demonstrating the distinct requirements for IFNγ and CD4 T cells in host defense against Chlamydia. In Rag1-deficient mice, IFNγ produced by innate lymphocytes (ILCs) accounted for early bacterial control and prolonged survival in the absence of adaptive immunity. Although type I ILCs are potent IFNγ producers, we found that mature NK cells and ILC1s were not the sole source for innate IFNγ in response to Chlamydia. By conducting T cell adoptive transfer, we showed definitively that IFNγ-deficient CD4 T cells were sufficient for effective bacterial killing in the FRT during the first 21 days of infection and reduced bacterial burden more than 1,000-fold, albeit mice receiving IFNγ-deficient CD4 T cells failed to completely eradicate the bacteria from the FRT like their counterparts receiving WT CD4 T cells. Together, our results revealed that innate IFNγ is essential for preventing systemic Chlamydia dissemination, whereas IFNγ produced by CD4 T cells is largely redundant at the FRT mucosa.

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“…Chlamydial vaccines have utilized numerous approaches to improve vaccine immunogenicity, including the use of plasmid DNA, recombinant proteins, and subunit antigenic determinants, with or without adjuvants, yet the need for effective preventive measures remains unmet (Brunham and Rey-Ladino, 2005;Vasilevsky et al, 2014). Studies have indicated a critical role for chlamydia-specific CD4 + Th1 T cell responses in the clearing of infection and provision of protective immunity against chlamydia reinfection (Su and Caldwell, 1995;Gondek et al, 2012;Bakshi et al, 2018;Labuda and McSorley, 2018). The chlamydial major outer membrane protein (MOMP) has been shown to induce an immune response comparable to that seen with live bacteria in mice (Pal et al, 2005), while polymorphic membrane proteins (PMPs), have been explored for their ability to induce crossspecies immunogenicity (Pal et al, 2017).…”

Section: Chlamydiamentioning

confidence: 99%

A Survey of Preclinical Studies Evaluating Nanoparticle-Based Vaccines Against Non-Viral Sexually Transmitted Infections

et al. 2021

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A worldwide estimate of over one million STIs are acquired daily and there is a desperate need for effective preventive as well as therapeutic measures to curtail this global health burden. Vaccines have been the most effective means for the control and potential eradication of infectious diseases; however, the development of vaccines against STIs has been a daunting task requiring extensive research for the development of safe and efficacious formulations. Nanoparticle-based vaccines represent a promising platform as they offer benefits such as targeted antigen presentation and delivery, co-localized antigen-adjuvant combinations for enhanced immunogenicity, and can be designed to be biologically inert. Here we discuss promising types of nanoparticles along with outcomes from nanoparticle-based vaccine preclinical studies against non-viral STIs including chlamydia, syphilis, gonorrhea, and recommendations for future nanoparticle-based vaccines against STIs.

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Diversity in the T cell response to Chlamydia-sum are better than one

Cited by 16 publications

References 70 publications

Th1 cells are dispensable for primary clearance of Chlamydia from the female reproductive tract of mice

Th1 cells are dispensable for primary clearance of Chlamydia from the female reproductive tract of mice

Innate IFN-γ Is Essential for Systemic Chlamydia muridarum Control in Mice, While CD4 T Cell-Dependent IFN-γ Production Is Highly Redundant in the Female Reproductive Tract

A Survey of Preclinical Studies Evaluating Nanoparticle-Based Vaccines Against Non-Viral Sexually Transmitted Infections

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