title: CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer.
abstract: Studies conducted in animal model of infectious diseases or H-Y antigen model suggest a crucial role for CD4+ T cells in providing help for CD8+ T-cell memory responses. This concept suggests that inclusion of T helper epitopes in vaccine formulation will result in improved CD8+ T-cell responses. Although this concept has been applied to cancer vaccine design, the role of CD4+ T cells in the memory differentiation of CD8+ T cells and retention of their anti-tumor function have never been tested in breast cancer model. Using the FVB mouse model of neu-positive breast carcinoma we report for the first time that helpless T cells showed cytostatic or tumor inhibitory effects during primary tumor challenge whereas, helped T cells showed cytotoxic effects and resulted in complete tumor rejection. Such differential effects, in vivo, were associated with higher frequency of CD8+PD-L1+ and CD8+PD-1+ T cells in animals harboring helpless T cells as well as higher titer of IL-2 in the sera of animals harboring helped T cells. However, depletion of CD4+ T cells did not alter the ability of neu-specific CD8+ T cells to differentiate into memory cells and to retain their effector function against the tumor during recall challenge. These results suggest the inhibitory role of CD4+ T cells on CD8+ T-cell exhaustion without substantial effects on the differentiation of memory T cells during priming phase of the immune responses against breast cancer.
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center, Box 980035, Richmond, VA 23298, USA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.forename: Andrea
authors.initials: A
authors.lastname: Worschech
authors.forename: Hooman
authors.initials: H
authors.lastname: Nikizad
authors.forename: Madhu
authors.initials: M
authors.lastname: Gowda
authors.forename: Mehran
authors.initials: M
authors.lastname: Habibi
authors.forename: Amy
authors.initials: A
authors.lastname: Depcrynski
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Kamar
authors.initials: K
authors.lastname: Godder
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Holt
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000276:immunology; D018920:Coculture Techniques; D045142:Cross-Priming; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D047368:Tumor Burden / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018960:Hyaluronan Receptors; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D053221:TNF-Related Apoptosis-Inducing Ligand; C476399:Cd44 protein, mouse; C506387:Cflar protein, mouse; C505654:Tnfsf10 protein, mouse