In the present study, we have examined the kinetics and magnitude of expression of the CD28 and CD152 molecules on unstimulated and anti-CD3 þ rIL-2-stimulated peripheral blood CD4 þ and CD8 þ T cells in patients with chronic lymphocytic leukaemia (B-CLL) and controls. The mean percentages of both CD3 þ /CD4 þ /CD28 þ and CD3 þ /CD8 þ /CD28 þ cells were significantly lower in B-CLL than in controls before culture, decreased rapidly, reaching their lowest levels between 24 and 48 h, and returned to basal levels after 72 h of culture. In controls, the lowest proportions of CD3 þ /CD4 þ /CD28 þ and CD3 þ /CD8 þ / CD28 þ cells were found after 24 h and returned to prestimulation levels after 48 h of stimulation. We observed significantly higher proportions of unstimulated CD3 þ /CD4 þ /CD152 þ and CD3 þ /CD8 þ /CD152 þ cells in B-CLL patients than in controls. The highest percentages of CD3 þ /CD4 þ /CD152 þ and CD3 þ /CD8 þ /CD152 þ cells were observed in controls after 72 h, and in B-CLL patients after 24 h, and remained statistically higher after 48, 72 and 96 h of stimulation. CD152 molecule expression returned to prestimulation levels after 96 h of culture in controls, and after 120 h in B-CLL patients. The abnormal kinetics and levels of CD28 and CD152 expression on T cells in B-CLL may lead to a state of hyporesponsiveness or anergy and could be one of the mechanisms of immune deficiency in this disease.
Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients’ T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients. Conclusions: Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression.
A number of phenotypic and functional alterations have been described in T cells of cancer patients. These changes are believed to reflect an impaired T-cell mediated immunity, which in turn, may result in a decreased capacity to generate an effective antitumor response. Several mechanisms have been proposed to explain depressed immunity in cancer patients including tumor-derived suppressor factors, abnormal cytokine production, deletion or inactivation of tumor-reactive T-cells. To investigate the mechanism underlying the immunodeficiency in Hodgkin's disease (HD) we studied the expression of T cell receptor zeta chain, which plays a vital role in the cascade of events leading to T and NK cell activation. The expression of the zeta chain of the T cell receptor/CD3 complex was analyzed by dual colour immunofluorescence on peripheral blood T lymphocytes: CD3+, CD4+, CD8+ and NK-cells (CD56+) in patients in different phases of the disease. Zeta chain was significantly reduced on CD3, CD4, CD8, and CD56 positive cells from patients in active phase of the disease compared with normal controls (p=0.05). In patients tested in complete clinical remission the values were normal except for the subpopulation of CD8+ cells in which the expression of zeta chain remained significantly reduced compared with controls. Downregulation of CD3/zeta-chain in PBLs and NK cells in active phase of HD- and to a lesser extent in clinical remission may contribute to immunodeficiency associated with the disease.
Summary. Expression of the downregulatory CTLA‐4 molecule was determined on unstimulated and anti‐CD3 + recombinant interleukin 2 (rIL‐2)‐stimulated peripheral blood T cells in Hodgkin's disease (HD) and correlated with the T‐cells' proliferative activity, IL‐2 and interferon (IFN)‐gamma production. There was a negligible percentage of CTLA‐4+/CD3+ cells before culture. The mean percentage of CTLA‐4+/CD3+ lymphocytes increased gradually, peaked after 72 h of stimulation and returned to basal values after 96 h of stimulation. The mean proportion of CTLA‐4+/CD3+ cells from untreated patients was significantly higher after 24, 48 and 72 h of stimulation compared with controls. The mean percentage of CTLA‐4+/CD3+ cells from patients in clinical remission (CR) was lower than that of untreated patients, but remained significantly higher compared with controls. Lymphocytes from untreated HD patients showed impaired proliferative activity, IL‐2 and IFN‐gamma production compared with controls. The proliferative activity of the lymphocytes, IL‐2 and IFN‐gamma production remained significantly lower in CR compared with controls. The proportion of CTLA‐4+/CD3+ cells negatively correlated with proliferative activity, IL‐2 and IFN‐gamma production in HD patients and controls. However, some untreated patients as well as patients in CR with normal mean fluorescence intensity values of CTLA‐4 showed unimpaired T‐cell function tests. Our study provides the first evidence of an increased expression of downregulatory CTLA‐4 molecule on stimulated T‐cells in HD, which could be one of the mechanisms of immune deficiency in this disease.
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