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Functional Heterogeneity of Vaccine-Induced CD8⁺ T Cells¹

Vladia Monsurrò^*, Dirk Nagorsen^*, Ena Wang^*, Maurizio Provenzano^*, Mark E. Dudley, Steven A. Rosenberg and Francesco M. Marincola^2,*

^* Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

The functional status of circulating vaccine-induced, tumor-specific T cells has been questioned to explain their paradoxical inability to inhibit tumor growth. We enumerated with HLA-A*0201/peptide tetramers (tHLA) vaccine-elicited CD8⁺ T cell precursor frequency among PBMC in 13 patients with melanoma undergoing vaccination with the HLA-A*0201-associated gp100:209–217(210 M) epitope. T cell precursor frequency increased from undetectable to 12,400 ± 3,600 x 10⁶ CD8⁺ T cells after vaccination and appeared heterogeneous according to previously described functional subtypes: CD45RA⁺CD27⁺ (14 ± 2.6% of tHLA-staining T cells), naive; CD45RA^-CD27⁺ (14 ± 3.2%), memory; CD45RA⁺CD27^- (43 ± 6%), effector; and CD45RA^-CD27^- (30 ± 4.1%), memory/effector. The majority of tHLA⁺CD8⁺ T cells displayed an effector, CD27^- phenotype (73%). However, few expressed perforin (17%). Epitope-specific in vitro stimulation (IVS) followed by 10-day expansion in IL-2 reversed this phenotype by increasing the number of perforin⁺ (84 ± 3.6%; by paired t test, p < 0.001) and CD27⁺ (from 28 to 67%; by paired t test, p = 0.01) tHLA⁺ T cells. This conversion probably represented a change in the functional status of tHLA⁺ T cells rather than a preferential expansion of a CD27⁺ (naive and/or memory) PBMC, because it was reproduced after IVS of a T cell clone bearing a classic effector phenotype (CD45RA⁺CD27^-). These findings suggest that circulating vaccine-elicited T cells are not as functionally active as inferred by characterization of IVS-induced CTL. In addition, CD45RA/CD27 expression may be more informative about the status of activation of circulating T cells than their status of differentiation.