Purpose: Patients with chronic lymphocytic leukemia (CLL) display immune deficiency that is most obvious in advanced stage disease. Here we investigated whether this immune dysfunction plays a pathologic role in the progression of early stage disease patients.Experimental Design: We carried out eight-color immunophenotyping analysis in a cohort of 110 untreated early stage CLL patients and 22 age-matched healthy donors and correlated our findings with clinical outcome data.Results: We found a significant reduction in naive CD4 þ and CD8 þ T cells in CLL patients. Only the CD4 þ subset showed significantly increased effector memory cells (T EM and T EMRA ) in the whole cohort (P ¼ 0.004 and P ¼ 0.04, respectively). However, patients with inverted CD4:CD8 ratios (52 of 110) showed preferential expansion of the CD8 compartment, with a skewing of CD8 þ T EMRA (P ¼ 0.03) coupled with increased percentage of CD57 þ CD28 À CD27 À T cells (P ¼ 0.008) and PD-1 positivity (P ¼ 0.027), consistent with a replicative senescence phenotype. Furthermore, inverted CD4:CD8 ratios were associated with shorter lymphocyte doubling time (P ¼ 0.03), shorter time to first treatment (P ¼ 0.03), and reduced progression-free survival (P ¼ 0.005). Conclusions: Our data show that the emergence of CD8 þ PD-1 þ replicative senescence phenotype in early stage CLL patients is associated with more aggressive clinical disease. Importantly, these findings were independent of tumor cell prognostic markers and could not be accounted for by patient age, changes in regulatory T-cell frequency, or cytomegalovirus serostatus. Clin Cancer Res; 18(3); 678-87. Ó2011 AACR.

HPV-16 is the major causes of cervical cancer. Persistence of infection is a necessary event for progression of the infection to cancer. Among other factors, virus persistence is due the viral proteins fighting the immune response. HPV-16 E5 down-regulates MHC/HLA class I, which is much reduced on the cell surface and accumulates in the Golgi apparatus in cells expressing E5. This effect is observed also in W12 cells, which mimic early cervical intraepithelial progression to cervical cancer. The functional effect of MHC I down-regulation on human CD8 T cells is not known, because of the need for HLA-matched, HPV-specific T cells that recognise E5 expressing-cells. Here we employ a heterologous cell/MHC I system which uses mouse cells expressing both E5 and HLA-A2, and A2-restricted CTLs; we show that the E5-induced reduction of HLA-A2 has a functional impact by reducing recognition of E5 expressing cells by HPV specific CD8+ T cells.

Understanding the extent to which genetic factors influence the immune response is important in the development of subunit vaccines. Associations with HLA gene polymorphisms appear insufficient to explain the range of variation in immune responses to vaccines and to infections by major pathogens. In this study of Gambian twins we report that regulation of the immune response to a variety of antigens from Plasmodium falciparum and Mycobacterium tuberculosis is controlled by factors which are encoded by genes that lie both within and outside the major histocompatibility complex (MHC). We define the relative contribution of these genes, which varies for different antigens. The cumulative genetic contribution of non-MHC genes to the total phenotypic variance exceeds that of the MHC-encoded genes.

Cancer cells frequently exhibit defects in apoptosis, which contribute to increased survival and chemotherapeutic resistance. For example, genetic mutations or abnormal proteasomal degradation can reduce expression of Bax which limits apoptosis. In cancers where abnormal proteasomal degradation of Bax occurs, we hypothesized that Bax peptides that bind to human leukocyte antigen (HLA) class I molecules would be generated for presentation to CD8 þ T cells. To test this hypothesis, we generated T cells against pooled Bax