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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.08-108274v1 22/10/3628    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Asprodites, N. Articles by Davila, E. PubMed PubMed Citation Articles by Asprodites, N. Articles by Davila, E.

Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity

Nicole Asprodites^*, Liqin Zheng^*, Degui Geng^*, Cruz Velasco-Gonzalez, Luis Sanchez-Perez and Eduardo Davila^*,,1

^* Stanley S. Scott Cancer Center,

School of Public Health, and

Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; and

Duke University Medical Center, Durham, North Carolina, USA

¹ Correspondence: Department of Pediatrics, CSRB Rm. 454, 533 Bolivar LSUHSC, New Orleans, LA 70112, USA. E-mail: edavil{at}lsuhsc.edu

Toll-like receptors (TLRs) are among the fundamental molecules that alert the immune system to the presence of an infection by recognizing pathogen-associated molecules. Much of our understanding regarding TLR function stems from the study of innate immune cells. Recent studies by several groups, including ours, have shown that TLRs can function as costimulatory receptors for antigen-specific T cells, resulting in enhanced T-cell survival and increased expression of effector molecules. We report that the ligation of the TLR1/2 heterodimer on OT-1 cytotoxic T-lymphocytes (CTL) but not TLR2^–/–OT-1 T cells increased cytolytic activity in vitro and in vivo. On the basis of these data, we tested the hypothesis that TLR1/2 stimulation on CTLs would enhance antitumor activity in a therapeutic model of B16-Ova melanoma. Adoptive OT-1 T-cell transfer into wild-type and MyD88^–/– mice, followed by injection with TLR1/2 ligand, resulted in a synergistic antitumor effect, which correlated with the induction of CD8 T cells specific to various tumor antigens. In contrast, mice receiving TLR2^–/–OT-1 T cells and TLR1/2 ligand showed minimal therapeutic efficacy. These findings emphasize the physiological significance of TLR2 engagement on CTLs and could make possible new approaches for the development of effective immunotherapies by manipulating TLR signaling within CTLs.—Asprodites, N., Zheng, L., Geng, D., Velasco-Gonzalez, C., Sanchez-Perez, L., Davila, E. Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity.

Key Words: T cell activation • costimulation • immunotherapy