Abstract
Patient with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Despite reported increases in absolute T cell counts in untreated patients with CLL, abnormalities of T cell phenotype and function have been described as well as progressive hypogammaglobulinemia. Furthermore, defects are compounded by current treatments for the disease. Expansion and differentiation of normal antigen-specific T cells depends upon two signals: binding of the T cell receptor to antigen presented in the context of self MHC molecules and ligation of a costimulatory receptor. CD28 is the primary T cell surface costimulatory receptor and is constitutively expressed on almost all CD4+ and about 50% of CD8+ T cells. The ligands CD80 and CD86 bind CD28, thereby transducing the second enhancing signal for T cell proliferation and cytokine secretion. CD152 (CTLA-4) has homology to CD28 and binds to CD80 and CD86 with much higher affinity, but plays a critical role in the down regulating T cell responses and maintenance of peripheral tolerance. Surface CD152 is not normally expressed on resting T cells, but is induced upon activation. We hypothesized that in previously untreated patients with CLL, T cell anergy is the result of increased expression of CD152. Therefore, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from blood (N=40) and bone marrow (N=14) of previously untreated patients with CLL. Also, the activation status of these T cells was evaluated by evaluating IL-2 receptor subunit expression. CD4+ and CD8+ T cells from patients with CLL demonstrated significant increase in sCD152 and cCD152 compared to T cells from normal donors (Table 1).
Table 1 Expression of CD152 by T Cells
Mean % Positive T Cell Population Normal CLL P-value sCD152 N=13 N=40 CD4+ 0.8 5.0 <.01 CD4+/CD25+ 1.8 11.5 <.05 CD8+ 1.8 5.0 <.05 cCD152 N=13 N=19 CD4+ 6.9 40.4 <.01 CD4+/CD25+ 26.6 48.0 <.01 CD8+ 1.3 16.9 <.05
Furthermore, patients with CLL had an increased proportion of CD4+/CD25+/CD152+ cells. This subpopulation of T cells is known to have a regulatory function. T cells from patients with CLL (N=25) also showed an activated immunophenotype with significantly increased proportion of CD4+ and CD8+ T cells co-expressing the CD122/CD25 subunits of the IL-2 receptor compared to normal donors (N=10). No significant differences were seen in proportion or pattern of expression of these antigens between peripheral blood and bone marrow cells. These findings suggest that the T cells have been activated, however, may be primed for hyporesponsiveness and peripheral tolerance by expression of CD152. Correlations between CD152 expression and relevant clinical and biological variables were made in these previously untreated patients. The number of CD4+/CD152+ and CD4+/CD25+/CD152+ cells from patients with CLL inversely correlated with serum IgG and IgA levels. These findings suggest a further possible involvement of CD152 in the possible suppression of normal B cells in patients with CLL. The proportion of CD4+/CD25+/CD152+ cells also correlated with advanced Rai stage. In summary, T cells from patients with CLL are potentially primed for anergy by expression of CD152. Functional studies to investigate the role of CD152 and CD4+/CD25+/CD152+ cells in patients with CLL are ongoing, with the goal to develop immunotherapeutic strategies.
IL-12 and IL-4 activate a CD39-dependent intrinsic peripheral tolerance mechanism in CD8+T cells
