Modulation of memory CD4 T cell function and survival potential by altering the strength of the recall stimulus.
Optimization of long term immunity depends on the functional persistence of memory T cells; however, there are no defined strategies for promoting memory T cell function and survival. In this study, we hypothesized that varying the strength of the recall stimulus could modulate the function and survival potential of memory CD4 T cells. We tested the ability of peptide variants of influenza hemagglutinin (HA) exhibiting strong and weak avidity for an HA-specific TCR, to modulate HA-specific memory CD4 T cells in vitro and in vivo. In vitro stimulation with a weak avidity peptide (L115) uncoupled memory CD4 T proliferation from effector cytokine production with low apoptosis, whereas stimulation with a strong avidity peptide (Y117) fully recalled memory T cell functions but triggered increased apoptosis. To determine how differential recall would affect memory T cells in vivo, we boosted BALB/c hosts of transferred, CFSE-labeled HA-specific memory CD4 T cells with native HA, Y117, and L115 variant peptides and found differences in early Ag-driven memory T cell proliferation and IL-7R expression, with subsequent changes in memory T cell yield. High avidity boosting resulted in rapid proliferation, extensive IL-7R down-regulation, and the lowest yield of HA-specific memory cells, whereas low avidity boosting triggered low in vivo proliferation, maintenance of IL-7R expression, and the highest memory T cell yield. Our results indicate that memory CD4 T cell function and survival can be modulated at the recall level, and can be optimized by low level stimulation that minimizes apoptosis and enhances responses to survival factors.
Patke
Deepa S
DS
Division of Transplantation, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Farber
Donna L
DL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory / Q000276:immunology*; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell