Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

Rahman, Anisur; Tiwari, Abhinav; Narula, Jatin; Hickling, Timothy P.

doi:10.1002/psp4.12352

Cited by 19 publications

(12 citation statements)

References 99 publications

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“…B-LCL cells alone were used as a control. Co-inhibitory molecules vary in their expression kinetics; whereas some molecules are expressed at early stages, others are expressed at the late stages of activation (66). Regardless of the infection status, increased HLA-G expression became apparent 3 h after exposure to PBMC and was sustained for at least 6 h (Figure 3D).…”

Section: Effect Of Hla-g Expression On Mait Cell Functionmentioning

confidence: 99%

B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor

et al. 2021

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Mucosal-associated invariant T (MAIT) cells are an innate-like population of T cells that display a TCR Vα7.2+ CD161+ phenotype and are restricted by the nonclassical MHC-related molecule 1 (MR1). Although B cells control MAIT cell development and function, little is known about the mechanisms underlying their interaction(s). Here, we report, for the first time, that during Salmonella enterica serovar Typhi (S. Typhi) infection, HLA-G expression on B cells downregulates IFN-γ production by MAIT cells. In contrast, blocking HLA-G expression on S. Typhi-infected B cells increases IFN-γ production by MAIT cells. After interacting with MAIT cells, kinetic studies show that B cells upregulate HLA-G expression and downregulate the inhibitory HLA-G receptor CD85j on MAIT cells resulting in their loss. These results provide a new role for HLA-G as a negative feedback loop by which B cells control MAIT cell responses to antigens.

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Section: Effect Of Hla-g Expression On Mait Cell Functionmentioning

confidence: 99%

B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor

et al. 2021

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“…We interpret the top (left) plateau in the level of PD-1 (Figure 5A) as corresponding to the homeostasis maintained by both the PD-1 DIFFL and the negative feedback activation of TCR which we discuss shortly below. At the same time the bottom (right) plateau in the level of PD-1 (Figure 5A) can be interpreted as an adaptation to high levels of Ag (3), a direct consequence of adaptive properties of IFFLs (6, 77–82).…”

Section: Resultsmentioning

confidence: 86%

Immunobiochemical Reconstruction of Influenza Lung Infection—Melanoma Skin Cancer Interactions

2019

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It was recently reported that acute influenza infection of the lung promoted distal melanoma growth in the dermis of mice. Melanoma-specific CD8+ T cells were shunted to the lung in the presence of the infection, where they expressed high levels of inflammation-induced cell-activation blocker PD-1, and became incapable of migrating back to the tumor site. At the same time, co-infection virus-specific CD8+ T cells remained functional while the infection was cleared. It was also unexpectedly found that PD-1 blockade immunotherapy reversed this effect. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates T cell pathways that control PD-1 expression. A core component of our model is a kinetic motif, which we call a PD-1 Double Incoherent Feed-Forward Loop (DIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the PD-1 DIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Collectively, the model allowed us to put forward a few working hypotheses as follows: (i) the melanoma-specific CD8+ T cells re-circulating with the blood flow enter the lung where they express high levels of inflammation-induced cell-activation blocker PD-1 in the presence of infection; (ii) when PD-1 receptors interact with abundant PD-L1, constitutively expressed in the lung, T cells loose motility; (iii) at the same time, virus-specific cells adapt to strong stimulation by their cognate antigen by lowering the transiently-elevated expression of PD-1, remaining functional and mobile in the inflamed lung, while the infection is cleared. The role that T cell receptor (TCR) activation and feedback loops play in the underlying processes are also highlighted and discussed. We hope that the results reported in our study could potentially contribute to the advancement of immunological approaches to cancer treatment and, as well, to a better understanding of a broader complexity of fundamental interactions between pathogens and tumors.

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“…When B memory cells emerge from a GC, they display a highly antigen-specific immunoglobulin on their surface which allows them to bind and present antigen to T cells. In the continuous presence of antigen, this positive feedback mechanism 20 could enable the generation of de novo GC reactions and antibody responses, whose accumulation would be restricted in VHL fl/fl ;Cγ1 +/cre mice.…”

Section: Discussionmentioning

confidence: 99%

Germinal center hypoxia in tumor-draining lymph nodes negatively regulates tumor-induced humoral immune responses in mouse models of breast cancer

et al. 2021

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Hypoxia develops in germinal centers (GCs) induced by model antigens; however, it is unknown whether tumor-reactive GCs are also hypoxic. We identified GC hypoxia in lymph nodes (LNs) draining murine mammary tumors and lethally irradiated tumor cells, and found that hypoxia is associated with the levels of antibody-secreting B cells. Hypoxic culture conditions impaired the proliferation of activated B cells, and inhibited class-switching to IgG1 and IgA immunoglobulin isotypes in vitro . To assess the role of the hypoxic response in tumor-reactive GCs in vivo , we deleted von Hippel-Lindau factor (VHL) in class-switched B cells and found decreased GC B cells in tumor-draining LNs, reduced class-switched and tumor-specific antibodies in the circulation, and modified phenotypes of tumor-infiltrating T cells and macrophages. We also detected the hypoxia marker carbonic anhydrase IX in the GCs of LNs from breast cancer patients, providing evidence that GC hypoxia develops in humans. We conclude that GC hypoxia develops in TDLNs, and that the hypoxic response negatively regulates tumor-induced humoral immune responses in preclinical models.

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Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

Cited by 19 publications

References 99 publications

B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor

B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor

Immunobiochemical Reconstruction of Influenza Lung Infection—Melanoma Skin Cancer Interactions

Germinal center hypoxia in tumor-draining lymph nodes negatively regulates tumor-induced humoral immune responses in mouse models of breast cancer

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