Regulation of CD4+ T Cell Responses During Chronic Viral Infection

Information

  • Research Project
  • 10322954
  • ApplicationId
    10322954
  • Core Project Number
    R21AI154916
  • Full Project Number
    3R21AI154916-02S1
  • Serial Number
    154916
  • FOA Number
    PA-18-926
  • Sub Project Id
  • Project Start Date
    6/18/2020 - 3 years ago
  • Project End Date
    5/31/2022 - 2 years ago
  • Program Officer Name
    JIANG, CHAO
  • Budget Start Date
    7/19/2021 - 2 years ago
  • Budget End Date
    5/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
    S1
  • Award Notice Date
    7/19/2021 - 2 years ago

Regulation of CD4+ T Cell Responses During Chronic Viral Infection

PROJECT SUMMARY Immunity to infectious disease and cancer is dependent on a robust T cell response to clear the pathogen or compromised cells and establish a memory population to protect against future challenge. Understanding T cell biology including T cell activation, differentiation, and memory formation can thus guide future studies on the development of novel therapies to augment this response and impact immunological memory. Although studies demonstrate the contributions of both CD4+ and CD8+ T cells to the effector response and memory formation with pathogenic infection, many are focused on the CD8+ T cell compartment and fail to appreciate the contribution(s) of CD4+ T cells. Our studies recently identified PSGL-1 as an inhibitory receptor expressed on T cells and showed that deletion of PSGL-1 led to reduced exhaustion in both the CD4+ and CD8+ T cell compartments in the context of chronic virus infection with LCMV clone 13 (Cl13). This is evidenced by the ability of PSGL-1-deficient mice to clear LCMV Cl13 infection much earlier than their wildtype counterparts. However, this ability to clear the chronic infection is lost upon CD4+ T cell depletion, demonstrating the importance of this population in the immune response necessary for the resolution of infection. We also found that CD4+ T cells, like CD8+ T cells, display greatly enhanced effector responses to acute infection with LCMV Armstrong, with greater persistence of functional memory cells. The goal of the studies presented in this proposal is to further elucidate the contribution(s) of CD4+ T cells in both acute and chronic infection and memory generation and to further understand how PSGL-1-deficiency confers the capability to clear infection. To this end, the contribution of PSGL-1 deficient CD4+ T cells will be assessed using adoptive transfer of antigen-specific PSGL-1 deficient CD4+ T cells. As the CD4+ T cells population forms a more heterogenous population that is known to change with the temporal progression of infection, single-cell sequencing will be used to identify changes in CD4+ T cells. PSGL-1-deficient mice are capable of clearing LCMV Cl13 which otherwise establishes a chronic infection in wildtype mice; the mechanism(s) by which this occurs will be interrogated by studying changes in motility with PSLG-1-deficiency and the impact of antigen load. As PSGL-1 has been demonstrated to affect T cell activation and function, it represents a therapeutic target for altering T cell differentiation and memory formation; conditional deletion and antibody mediated modulation of PSGL-1 signaling will be studied in both acute and chronic models of infection to further elucidate the role PSGL-1 plays in the T cell compartment. The studies presented here offer a means to understand how modulation of PSGL-1 signaling could augment T cell function and memory generation and impact on the ability of CD4+T cells to augment CD8+ T cell responses that could be used in context of infection and cancer as well as vaccine design to improve overall immunity.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R21
  • Administering IC
    AI
  • Application Type
    3
  • Direct Cost Amount
    48543
  • Indirect Cost Amount
    46116
  • Total Cost
    94659
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:94659\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES