Rescue of CD8 T cell-mediated antimicrobial immunity with a nonspecific inflammatory stimulus.
Reconstitution of protective immunity by adoptive transfer of pathogen-specific T cells has been successful in patients with compromised cellular immunity. The in vivo effectiveness of in vitro-expanded CD8 CTLs is variable, however. For example, adoptively transferred Listeria monocytogenes-specific CD8 CTLs only confer protective immunity if challenge infection occurs within 48 hours of T cell infusion. Herein we show that transferred CTLs persist in lymphoid compartments for many weeks, but that their response to bacterial challenge decreases during the first week following transfer. While T cells transferred less than 48 hours before infection proliferate, those transferred 7 days before infection die. Remarkably, treatment of mice with anti-CD40 at the time of T cell infusion reprograms transferred T cells, allowing them to proliferate and confer protective immunity upon bacterial challenge 7 days later. Our study demonstrates, for the first time to our knowledge that CD40-mediated stimuli can influence CD8 T cell activation independent of concurrent antigen exposure. The ability to modulate long-term responsiveness of CD8 T cells with a transient, nonspecific inflammatory stimulus has importation implications for adoptive immunotherapy.
Tuma
Roman A
RA
Infectious Disease Service, Department of Medicine and Immunology Program, Memorial Sloan-Kettering Institute, New York, New York 10021, USA. tumar@mskcc.org
Giannino
Rielle
R
Guirnalda
Patrick
P
Leiner
Ingrid
I
Pamer
Eric G
EG
D000818:Animals; D000942:Antigens, Bacterial; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C
D000942:Antigens, Bacterial; D019013:CD40 Antigens; D016056:Immunodominant Epitopes