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Sensitivity of Undifferentiated, High-TCR Density CD8⁺ Cells to Methylene Groups Appended to Tumor Antigen Determines Their Differentiation or Death

Departments of ¹ Gynecologic Oncology, ² Breast Medical Oncology, and ³ Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁴ Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and ⁵ Infectious Disease Research Institute, Seattle, Washington

Requests for reprints: Constantin G. Ioannides, Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Unit 440, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2849; Fax: 713-792-3575; E-mail: cioannid{at}mdanderson.org .

CD8⁺ cells expressing high numbers of TCR per cell (TCR^hi) are considered important mediators of antitumor effects. To understand the relationship between TCR density and antigen affinity for TCR in the outcome of stimulation with antigen and differentiation of CTL recognizing tumor antigen, we analyzed perforin induction in ovarian tumor-associated lymphocytes in response to the smallest possible changes in the atomic forces of interaction between antigen and TCR. Stimulating undifferentiated, apoptosis-resistant CD8⁺ cells expressing high levels of E75-TCR (TCR^hi) with variants of the CTL epitope E75, HER-2 (369-377), induced their stepwise differentiation, first to IFN-⁺ Perf^– and to TCR^hi IFN-⁺ Perf⁺ cells. Blocking caspase-9 activation at antigen stimulation also enhanced the generation of TCR^hi Perf^hi cells, demonstrating that TCR density dictated the pathway of death activated by stimulation with the same agonist. Expansion and differentiation of TCR^hi Perf⁺ CTL required an agonist of optimal CH₂ side chain length, which in this study was equal to two CH₂ groups appended to E75 at the Gly⁴ position. Side chains one CH₂ shorter or longer than optimal were either less stimulatory or induced death of TCR^hi Perf⁺ cells. Differentiation of TCR^hi CD8⁺ cells can be finely tuned by synthetic amino acids in the peptide, whose side chains induce small increments in the affinity of the antigen for TCR below the affinity which induce apoptosis.

Key Words: CTL • perforin • TCR • synthetic amino acids • HER-2

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