title: Memory Th1 cells augment tumor-specific CTL following transcutaneous peptide immunization.
abstract: Targeting dendritic cells in vivo by transcutaneous peptide immunization (TCI) represents an efficient immunization strategy to induce tumor-specific CTL because it reflects the physiologic conditions occurring during pathogen infection. Here we show that including a Th1 peptide in TCI can activate preexisting memory Th1 (mTh1) responses and thereby enhance the CTL response. For this purpose, peptide-25, a major Th1 epitope of Ag85B from Mycobacterium tuberculosis, was selected. We adoptively transferred peptide-25-specific mTh1 cells and hgp100-specific naive CTL (pmel-1 TCR transgenic) into C57BL/6 mice. Subsequently, mice were transcutaneously immunized with CTL peptide (hgp100) and Th1 peptide (peptide-25). Five days after TCI, the frequency and function of pmel-1 cells was monitored by intracellular IFN-gamma staining, ELISPOT, and in vivo cytotoxicity assays. TCI efficiently expanded hgp100-specific, IFN-gamma-producing, strongly cytotoxic CD8(+) T cells. Concurrent activation of mTh1 cells by peptide-25 induced a 1.5-fold increase in the number of hgp100-specific CTL with enhanced effector functions. Furthermore, TCI elicited not only prophylactic but also therapeutic antitumor responses that were augmented by peptide-25. These results show that TCI facilitates peptide-specific activation of CD4(+) T cells, responsible for the augmenting effect of peptide-25 on the hgp100-specific CTL response. Because a significant proportion of the Japanese population has been vaccinated with Bacillus Calmette-Guerin, they are likely to possess Ag85B- or peptide-25-specific mTh1 cells. Therefore, concomitant activation of Ag85B- or peptide-25-specific mTh1 cells together with tumor-specific CTL by TCI might augment antitumor immune responses in a sizeable fraction of patients.
authors.affiliation: Department of Immunotherapeutics (Medinet), Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hosoi
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Takeda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Furuichi
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurachi
authors.forename: Kiminori
authors.initials: K
authors.lastname: Kimura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Maekawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakimi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D000939:Epitopes / Q000737:chemistry; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry*; D012878:Skin Neoplasms / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D000939:Epitopes; D010455:Peptides; D007371:Interferon-gamma