Browsing by keyword "ThCTL"

Now showing items 1-2 of 2

    • Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15 [preprint]
      Devarajan, Priyadharshini; Vong, Allen M.; Castonguay, Catherine H.; Silverstein, Noah J.; Kugler-Umana, Olivia; Bautista, Bianca L.; Kelly, Karen A.; Luban, Jeremy; Swain, Susan L. (2022-10-13)
      Cytotoxic CD4 T cells (ThCTL) are tissue-resident effectors that enhance viral clearance by MHC-II-restricted cytotoxicity of infected cells. Using a model of influenza A virus (IAV) infection, we identify key factors that drive CD4 effectors to differentiate into lung-resident ThCTL. We find that, to become ThCTL, CD4 effectors must again recognize cognate antigen on antigen presenting cells (APC) within the lung. Different APC subsets can drive this transition, including dendritic cells, B cells, and to a lesser extent non-hematopoietic MHC-II+ APC. CD28 co-stimulation is not required and can reduce ThCTL development. In contrast, T follicular helper cells (TFH) that are another specialized CD4 effector subset, require CD28 during this time. Optimal ThCTL generation also requires ongoing infection in the effector phase, that acts independently of antigen presentation. The mechanism involves production of Type I IFN, that induces IL-15 which acts to support further differentiation of CD4 effectors to ThCTL. The multiple spatial, temporal and cellular requirements for ThCTL generation from CD4 effectors described here would be expected to prevent cytotoxic CD4 responses in the lung after pathogen has already been cleared, while ensuring the development of potent lung-restricted ThCTL effectors when pathogen persists.

    • Pathogen Recognition by CD4 Effectors Drives Key Effector and Most Memory Cell Generation Against Respiratory Virus
      Devarajan, Priyadharshini; Jones, Michael C.; Kugler-Umana, Olivia; Vong, Allen M.; Xia, Jingya; Swain, Susan L. (2018-03-26)
      Although much is known about the mechanisms by which pathogen recognition drives the initiation of T cell responses, including those to respiratory viruses, the role of pathogen recognition in fate decisions of T cells once they have become effectors remains poorly defined. Here, we review our recent studies that suggest that the generation of CD4 T cell memory is determined by recognition of virus at an effector "checkpoint." We propose this is also true of more highly differentiated tissue-restricted effector cells, including cytotoxic "ThCTL" in the site of infection and TFH in secondary lymphoid organs. We point out that ThCTL are key contributors to direct viral clearance and TFH to effective Ab response, suggesting that the most protective immunity to influenza, and by analogy to other respiratory viruses, requires prolonged exposure to antigen and to infection-associated signals. We point out that many vaccines used today do not provide such prolonged signals and suggest this contributes to their limited effectiveness. We also discuss how aging impacts effective CD4 T cell responses and how new insights about the response of aged naive CD4 T cells and B cells might hold implications for effective vaccine design for both the young and aged against respiratory viruses.