Pathogen Recognition by CD4 Effectors Drives Key Effector and Most Memory Cell Generation Against Respiratory Virus

Abstract

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.

“An Intrinsic Program Determines Key Age-Associated Changes in Adaptive Immunity That Limit Response to Non-Pathogens”

“…Ongoing infection is also necessary. Thus high systemic PR signals are needed both to activate the APC to drive TFH development and to induce yetto-be determined innate pathways (Devarajan et al, 2018;Devarajan et al, 2020). While these studies are in young mice, we predict these PR signals will be of equal or greater importance in aged mice, due to the need for higher IL-6 levels to stimulate aged naïve T cells (Figure 1B).…”

“…Indeed, adding activated APC at the effector phase enhances memory generation to inactivated influenza (Xia et al, 2020). Moreover, to drive further TFH effector responses, Ag on activated APCs needs to be present locally where the TFH reside (Devarajan et al, 2018;Devarajan et al, 2020). Ongoing infection is also necessary.…”

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

“…Through thymic selection, CD4/CD8 double positive T cells develop into either mature CD4 (helper) or CD8 (cytotoxic) T cells, which recognize major histocompatibility complex (MHC) class II (MHCII)/peptide and MHCI/peptide complexes, respectively (Figure 1). However, some mature CD4 T cells, cytotoxic CD4 T cells (CD4-CTLs or Th-CTLs), may act similarly as cytotoxic CD8 T cells in killing their target cells through the secretion of granzyme B and perforin but in an MHCII-restricted manner [13][14][15]. The transcriptional factor Eomes (a T-box transcription factor critical for the development of functional natural killer (NK) and CD8 T cells), T-bet, and Blimp1 are critical for inducing the expression of cytotoxicity-associated genes in CD4-CTLs [16][17][18].…”

Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15

“…Likewise, the generation of ThCTL correlated with their cytotoxic function against target cells ( Figure 1E). Tissue-restricted effector functions are critical to immunity (Devarajan et al, 2018).…”