TCells

In addition to the polyclonal B-cell defects noted in patients with B-CLL, numerical and functional abnormalities exist in the T (CD3+) cell population in these patients. Because of the increased number of malignant B-cells, the percentage of T-lymphocytes is reduced; however, the absolute number of blood T-lymphocytes is often increased. Interestingly, a relative decrease in CD4+ T-cells is noted, with a relative increase in CD8+ T-cells in these patients (33; Table 3). A possible factor in the development of this CD4+ T-cell deficit may relate to the membrane expression of CD95 discussed above. Work by Tinhofer et al. (17) identified increased levels of CD95 (Fas) on the surface of CD4+ T-cells and CD8+ T-cells derived from patients with B-CLL (17). Stimulation of CD95 with monoclonal antibodies to Fas resulted in apoptosis of the CD4+ T-cells, but not the CD8+ T-cells.

Early studies identified oligoclonal T-cell populations in the blood of most B-CLL patients, utilizing molecular cloning techniques that detail the T-cell receptor repertoire (34,35). Further investigation with polymerase chain reaction (PCR) identified oligoclonal expansion in both the CD4+ and CD8+ T-cell subsets (36,37). Although initial studies by Rezany et al. (36) suggested that the T-cell clonality occurred primarily within the CD4+ T-cell subset, more recent studies have suggested that these perturbations are primarily restricted to the CD8+ T-cell population (38). In this study, Goolsby et al. (38) used multicolor flow cytometric techniques to assess the presence of oligoclonal T-cell populations directly in the blood of B-CLL patients. Nine of 19 patients were found to have clonal/oligoclonal expansion of a T-cell subset, based on flow cytometry. Molecular analysis of the T-cell receptor gene utilizing PCR was used to complement these findings. Of the 16 patients who underwent molecular testing, 12 were found to have clonal/oligoclonal patterns. In addition, based on the flow cytometric analysis, it was demonstrated that this occurred primarily within the CD8+ T-cell subset. It is perhaps relevant that certain T-cell subsets with oligoclonal expansion in the CD8+ T-cell population may be associated with an increased risk of disease progression in early-stage B-CLL (R.L. Bjork, Jr., personal communication).

Expansion of CD8+ T-cells detected by other methods have been described in B-CLL. Two separate investigations (39,40) demonstrated the presence of CD8+ B-CLL T-cells with a polarized cytokine profile for IL-4. In addition these T-cells were able to release IL-4 spontaneously. Since the latter cytokine is able to enhance CLL B-cell resistance to apoptosis, it is possible this unique T-helper-like CD8+ cell is important in maintaining CLL B-cell apoptosis resistance. Indeed, the production of IL-4 has been noted for CLL CD8+ T-cells and also the CLL B-cell (41). The presence of IL-4 in CLL B-cells and blood CD8+ T-cells from B-CLL patients (41) strongly suggests that the cytokine microenvironment in a B-CLL patient may be favorable for maintenance of CLL B-cell apoptosis. The presence of membrane receptors for IL-4 (41) on CLL B-cells indicates they are capable of binding IL-4 and generating downstream cytoplasmic and nuclear changes that could enhance their resistance to apoptosis and/or drug resistance. The latter alterations may occur because of increased expression of Bcl-2 (42) and/or protection against APO-1-induced apoptosis, which are both biological events shown to result following exposure of leukemic CLL B-cells to IL-4 (43).

Other T-cell cytokines may be relevant to the biology of the B-CLL B-cells. Thus, IL-2 can induce proliferation of the B-CLL B-cells in vitro (44). IL-2, as well as IL-4 and interferon gamma inhibit apoptosis of the leukemic B-cells (42,45,46), whereas IL-5 and IL-10, induce apoptosis of the leukemic B-cells (47,48). TNF-a can induce proliferation of the leukemic B-cells and is thought to play a role in disease progression (49). Investigation into the in vitro production of cytokines by T-cells of patients with B-CLL has identified increased levels not only of IL-4 but also of TFN-a, with decreased levels of IL-10 relative to normal controls (50). These T-cell derived cytokines individually or in a complex network may play an important role in the survival of B-CLL B-cells. It is also likely that the T-cell cytokine profile will vary depending on the tissue sites (i.e., marrow, node) of B-CLL patients.

Numerous studies using flow cytometry and immunohistochemistry have investigated the surface expression of T-cell-associated antigens, including critical activation and interaction markers, on the blood T-cells of patients with B-CLL. When compared with normal controls, there is a decrease in the number of T-cells expressing CD25 (IL-2 receptor protein), CD28, CD4, CD5, CD11a, and CD152. This has been associated with a notable increase in the number of T-cells expressing HLA-DR (51,52). This aberrant membrane expression pattern provides additional evidence of immune dysregulation within the T-cell population in B-CLL. Since some CD4+ T-cells in B-CLL express CD25, this raises the possibility that CLL patients harbor significant numbers of the now well-characterized CD4+, CD25+suppressor cell (53). These T-cells are not conventional memory cells but regulatory cells with the ability to suppress the activation and proliferation of CD4+ and CD8+ T-cells. Although these latter T-cells have been seen in healthy normals, their presence in B-CLL could relate to the cellular immunodeficiency of this disease.

A recent report has shown no expression of surface CD152 (CTLA-4) on the circulating T-cells in a significant cohort of patients with B-CLL (51). The possible mechanism for this was reviewed in Subheading 3.1. above. Since CD152 plays a key role in immune regulation via a negative feedback ("switch-off") signal to the T-cell, once an immune response has been initiated or is ongoing, this latter finding may also be relevant to some of the autoimmune complications seen in B-CLL.

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