Reassessing the Transcriptional Regulation of Protective CD4 T Cell Responses Against Influenza A Virus

An attractive strategy to improve efficacy of current Influenza A Virus (IAV) vaccines is to promote protective CD4 T cell responses. Antiviral CD4 T cell responses are predominantly classified as strong IFN-gamma producing T helper type 1 (Th1) cells. Yet, the role of IFN-gamma in protection against IAV is still unclear, suggesting absolute Th1 polarization may be expendable for effective IAV immunity. Here we test this hypothesis using models that restrict the deficiency of known transcriptional regulators of Th1 immunity in only CD4 T cells, avoiding indirect impact on other immune cell responses. We find the \u27master regulator\u27 of Th1 cells, the T-box transcription factor T-bet (Tbx21), to be dispensable for CD4 T cell-mediated protection from lethal IAV but important for maximizing the magnitude of effector responses by regulating cell trafficking to the lung. While donor Tbx21-/- responses gain Th17 characteristics, they still produce substantial IFN-gamma, suggesting their Th1 attributes may still be required for protection. Interestingly, Tbx21-/- cells expressed more Eomesodermin (Eomes), a paralog of T-bet, but Eomes-/- cells retain WT-like responses suggesting minor roles for Eomes in presence of T-bet. In contrast, Tbx21-/-Eomes-/- cells, completely lose their Th1 identity but remarkably exhibit stronger inflammation-induced Th17 attributes than Tbx21-/- cells. Strikingly, we find in vitro Th17-primed Tbx21-/-Eomes-/- effectors lose their plasticity to become Th1 but instead strengthen their Th17-ness in IAV infected mice but still protect. Finally, we observed that protection of previously primed Tbx21-/- and Tbx21-/-Eomes-/- mice from a lethal unrelated IAV strain required T cell mediated immunity. Our observations thus demonstrate novel roles for Eomes in broadening the scope of protective mechanisms against IAV. Furthermore, we decisively demonstrate protective roles for prototypical non-plastic Th17 responses in primary and secondary responses, thus increasing the scope of target mechanisms relevant for CD4 T-cell based vaccination strategies against viral pathogens

Early Programming And Late-Acting Checkpoints Governing The Development Of Cd4 T-Cell Memory

CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T-cell generation into vaccine strategies therefore offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long-term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin-2, antigen and co-stimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through ‘programming’ that occurs during initial priming, and second, through ‘checkpoints’ that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin-2-, antigen- and co-stimulation-dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells

Regulation of CD4 T Cell Responses by the Transcription Factor Eomesodermin

Central to the impacts of CD4 T cells, both positive in settings of infectious disease and cancer and negative in the settings of autoimmunity and allergy, is their ability to differentiate into distinct effector subsets with specialized functions. The programming required to support such responses is largely dictated by lineage-specifying transcription factors, often called ‘master regulators’. However, it is increasingly clear that many aspects of CD4 T cell immunobiology that can determine the outcomes of disease states involve a broader transcriptional network. Eomesodermin (Eomes) is emerging as an important member of this class of transcription factors. While best studied in CD8 T cells and NK cells, an increasing body of work has focused on impacts of Eomes expression in CD4 T cell responses in an array of different settings. Here, we focus on the varied impacts reported in these studies that, together, indicate the potential of targeting Eomes expression in CD4 T cells as a strategy to improve a variety of clinical outcomes

A Rapid Blood Test To Determine The Active Status And Duration Of Acute Viral Infection

The ability to rapidly detect and diagnose acute viral infections is crucial for infectious disease control and management. Serology testing for the presence of virus-elicited antibodies in blood is one of the methods used commonly for clinical diagnosis of viral infections. However, standard serology-based tests have a significant limitation: they cannot easily distinguish active from past, historical infections. As a result, it is difficult to determine whether a patient is currently infected with a virus or not, and on an optimal course of action, based off of positive serology testing responses. Here, we report a nanoparticle-enabled blood test that can help overcome this major challenge. The new test is based on the analysis of virus-elicited immunoglobulin G (IgG) antibody present in the protein corona of a gold nanoparticle surface upon mixing the gold nanoparticles with blood sera. Studies conducted on mouse models of influenza A virus infection show that the test gives positive responses only in the presence of a recent acute viral infection, approximately between day 14 and day 21 following the infection, and becomes negative thereafter. When used together with the traditional serology testing, the nanoparticle test can determine clearly whether a positive serology response is due to a recent or historical viral infection. This new blood test can provide critical clinical information needed to optimize further treatment and/or to determine if further quarantining should be continued

Cigarette Smoke Extract Acts Directly On Cd4 T Cells To Enhance Th1 Polarization And Reduce Memory Potential

Although cigarette smoke is known to alter immune responses, whether and how CD4 T cells are affected is not well-described. We aimed to characterize how exposure to cigarette smoke extract impacts CD4 T cell effector generation in vitro under Th1-polarizing conditions. Our results demonstrate that cigarette smoke directly acts on CD4 T cells to impair effector expansion by decreasing division and increasing apoptosis. Furthermore, cigarette smoke enhances Th1-associated cytokine production and increases expression of the transcription factor T-bet, the master regulator of Th1 differentiation. Finally, we show that exposure to cigarette smoke extract during priming impairs the ability of effectors to form memory cells. Our findings thus demonstrate that cigarette smoke simultaneously enhances effector functions but promotes terminal differentiation of CD4 T cell effectors. This study may be relevant to understanding how smoking can both aggravate autoimmune symptoms and reduce vaccine efficacy

A Rapid Blood Test To Determine the Active Status and Duration of Acute Viral Infection

The ability to rapidly detect and diagnose acute viral infections is crucial for infectious disease control and management. Serology testing for the presence of virus-elicited antibodies in blood is one of the methods used commonly for clinical diagnosis of viral infections. However, standard serology-based tests have a significant limitation: they cannot easily distinguish active from past, historical infections. As a result, it is difficult to determine whether a patient is currently infected with a virus or not, and on an optimal course of action, based off of positive serology testing responses. Here, we report a nanoparticle-enabled blood test that can help overcome this major challenge. The new test is based on the analysis of virus-elicited immunoglobulin G (IgG) antibody present in the protein corona of a gold nanoparticle surface upon mixing the gold nanoparticles with blood sera. Studies conducted on mouse models of influenza A virus infection show that the test gives positive responses only in the presence of a recent acute viral infection, approximately between day 14 and day 21 following the infection, and becomes negative thereafter. When used together with the traditional serology testing, the nanoparticle test can determine clearly whether a positive serology response is due to a recent or historical viral infection. This new blood test can provide critical clinical information needed to optimize further treatment and/or to determine if further quarantining should be continued