Dendritic cell-mediated responses to secreted Cryptosporidium effectors promote parasite-specific CD8+ T cell responses

Mucosal Immunol. 2024 Jun;17(3):387-401. doi: 10.1016/j.mucimm.2024.03.003. Epub 2024 Mar 18.

Abstract

Cryptosporidium causes debilitating diarrheal disease in patients with primary and acquired defects in T cell function. However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, Cryptosporidium was engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8+ T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+ T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8+ T cell responses to these model antigens. These data sets highlight Cryptosporidium effectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8+ T cell responses to Cryptosporidium.

MeSH terms

  • Animals
  • Antigens, Protozoan / immunology
  • CD8-Positive T-Lymphocytes* / immunology
  • Cryptosporidiosis* / immunology
  • Cryptosporidium* / immunology
  • Dendritic Cells* / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Humans
  • Interferon-gamma / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / parasitology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protozoan Proteins / immunology
  • Protozoan Proteins / metabolism

Substances

  • Interferon-gamma
  • Protozoan Proteins
  • Antigens, Protozoan
  • Epitopes, T-Lymphocyte