Differentiation of Distinct Long-Lived Memory CD4 T Cells in Intestinal Tissues After Oral Listeria Monocytogenes Infection

Mucosal Immunol. 2017 Mar;10(2):520-530. doi: 10.1038/mi.2016.66. Epub 2016 Jul 27.


Mucosal antigen-specific CD4 T-cell responses to intestinal pathogens remain incompletely understood. Here we examined the CD4 T-cell response after oral infection with an internalin A 'murinized' Listeria monocytogenes (Lm). Oral Lm infection induced a robust endogenous listeriolysin O (LLO)-specific CD4 T-cell response with distinct phenotypic and functional characteristics in the intestine. Circulating LLO-specific CD4 T cells transiently expressed the 'gut-homing' integrin α4β7 and accumulated in the intestinal lamina propria and epithelium where they were maintained independent of interleukin (IL)-15. The majority of intestinal LLO-specific CD4 T cells were CD27- Ly6C- and CD69+ CD103- while the lymphoid LLO-specific CD4 T cells were heterogeneous based on CD27 and Ly6C expression and predominately CD69-. LLO-specific effector CD4 T cells transitioned into a long-lived memory population that phenotypically resembled their parent effectors and displayed hallmarks of residency. In addition, intestinal effector and memory CD4 T cells showed a predominant polyfunctional Th1 profile producing IFNγ, TNFα, and IL-2 at high levels with minimal but detectable levels of IL-17A. Depletion of CD4 T cells in immunized mice led to elevated bacterial burden after challenge infection highlighting a critical role for memory CD4 T cells in controlling intestinal intracellular pathogens.

MeSH terms

  • Administration, Oral
  • Animals
  • Antigens, CD / metabolism
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / immunology
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / metabolism
  • Heat-Shock Proteins / immunology
  • Hemolysin Proteins / immunology
  • Immunologic Memory*
  • Integrin alpha4 / metabolism
  • Integrin beta Chains / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism*
  • Listeria monocytogenes / immunology*
  • Listeriosis / immunology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Lymphocyte Homing / metabolism
  • Th1 Cells / immunology*


  • Antigens, CD
  • Bacterial Proteins
  • Bacterial Toxins
  • Cytokines
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • Integrin beta Chains
  • Receptors, Lymphocyte Homing
  • integrin beta7
  • internalin protein, Bacteria
  • Integrin alpha4
  • hlyA protein, Listeria monocytogenes