Dysregulated expression of both the costimulatory CD28 and inhibitory CTLA-4 molecules in PB T cells of advanced cervical cancer patients suggests systemic immunosuppression related to disease progression.

UNLABELLED: 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.

CD28 downregulation on CD4+ T cells is associated with age of kidney transplant recipient.

There is a growing body of evidence showing that the intensity of rejection is weaker in older kidney allograft recipients while chronic complications, but not rejection, are the main causes of graft loss. To investigate whether the age of the recipient is a factor affecting the expressions of the CD28, CTLA-4, and CD40L costimulatory molecules on CD4+ T cells. Their expression levels were determined in 78 kidney transplant recipients aged 17-68 years. The expression was assessed on unstimulated and anti-CD3 antibody + IL-2-stimulated CD4+ T cells. Median time after transplantation was 20 months and median serum creatinine was 1.5 mg/dl. Significant correlations between age and CD28 expression (r = -0.4, P = 0.0004) on CD4+ T cells and between age and CTLA-4 expression after stimulation (r = 0.34, P = 0.008) were found. CD40L expression on CD4+ T cells was not affected by recipient age. The decreased expression of CD28 and enhanced expression of CTLA-4 (after stimulation) associated with age may be helpful in transplant acceptance.

CD40L, CD28, and CTLA-4 expression on CD4+ T cells in kidney graft recipients: a relationship with post-transplantation clinical course.

BACKGROUND: Experimental studies have demonstrated that the intensity of alloreactivity against a transplanted organ results from an interaction of positive (CD40/CD40L and B.7/CD28) and inhibitory (B.7/CTLA-4) signals between antigen-presenting cells (APCs) and T lymphocytes. METHODS: We examined the CD40L, CD28, and both surface (s) and intracellular (i) CTLA-4 expressions on freshly drawn and anti-CD3+rIL-2-stimulated peripheral blood CD4+ T cells in groups of kidney transplant recipients in relation to distinct clinical course using the tri-color immunofluorescence method. RESULTS: The median proportions of freshly isolated CD3+/CD4+/CTLA-4+ and CD3+/CD4+/CD40L+ cells in all groups of graft recipients were higher than in control subjects. In patients with stable graft function (SGF), non-significantly higher sCTLA-4, significantly higher iCTLA-4 expression, and significantly lower CD40L expression on freshly drawn CD4+ T cells compared with recipients with chronic allograft nephropathy (CAN) were found. Moreover, CD4+ T cells from SGF patients showed a higher potential to express sCTLA-4 and CD40L molecules and to down-regulate the CD28 molecule in response to ex vivo stimulation than those from patients with CAN. In patients without acute graft rejection (NAGR), a markedly higher proportion of freshly drawn CD3+/CD4+/iCTLA-4+ cells compared with patients with acute graft rejection (AGR) and an up-regulation of the median percentage of CD3+/CD4+/CD40L+ cells after ex vivo stimulation was found. CONCLUSIONS: In patients with SGF, peripheral blood CD4+ T cells exhibited a higher potential to express surface CTLA-4 and CD40L and to down-regulate CD28 costimulatory molecules in response to ex vivo stimulation, indicating a relationship between the expression patterns of both costimulatory and inhibitory molecules in CD4+ T cells and clinical course after renal transplantation.

Lack of association between an exon 1 CTLA-4 gene polymorphism A(49)G and multiple sclerosis in a Polish population of the Lower Silesia region.

Multiple sclerosis (MS) a chronic inflammatory demyelinating disease of the central nervous system is believed to have a T cell-mediated autoimmune etiology. The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene is a strong candidate for the involvement in autoimmune diseases because CTLA-4 plays an important role in the downregulation of the early and late stages of T cell activation and the maintenance of peripheral T cell tolerance. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed an exon 1 CTLA-4 gene polymorphism A(49)G in 102 unrelated Polish MS patients in the Lower Silesia region and 101 age- and sex-matched healthy subjects. The distribution of CTLA-4 exon 1 A(49)G genotype, phenotype and allele frequencies did not differ between patients with MS and healthy subjects.

[Structure and function of lymphocyte TCR/CD3 complex]. / Struktura i funkcja kompleksu TCR/CD3 limfocytu T.

The multi-chain T cell receptor/CD3 complex (TCR/CD3) plays a key role in antigen recognition, T cell activation and in consequence in triggering an antigen specific immune response. This process is induced by direct interaction of the TCR receptor with an antigen bound to the major histo-compatible complex on antigen-presenting cells. Upon the structural and functional cooperation of TCR receptor with CD3 complex, the activating signal is transmitted through the cell membrane to the nucleus. The pivotal role in signaling cascade plays CD3-zeta (zeta) chain, which triggers many biochemical events and second messenger activation, leading to the transcriptional factors expression and further T cell proliferation, effector function augmentation and cytokine production.

Correlation of blood lymphocyte CTLA-4 (CD152) induction in Hodgkin's disease with proliferative activity, interleukin 2 and interferon-gamma production.

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.

CD28 costimulatory molecule--expression, structure and function.

T cell activation is a key event in triggering an antigen specific immune response of the organism. The process is induced primarily by the signal generated by direct interaction of a T cell receptor with an antigen bound to the major histocompatibile complex on an antigen-presenting cell (APC). Although the signal is critical in exciting immune response, an additional, costimulating signal is required. The major second signal is generated by interaction of the CD28 molecule expressed on most T lymphocytes with its natural ligands CD80 and CD86 located on APCs. The signal excited by CD28 triggering involves multiple second-messenger cascades, leading to the activation of transcription factors and finally results in cell proliferation, cytokine production, and the generation of effector functions. The importance of CD28-delivered costimulatory signals was proven in experiments with CD28-deficient mice. T cells from these mice exhibited an impaired pattern of cytokine secretion and defects in T cell-dependent antibody production. Certain forms of immunopathology might result from the aberrant regulation of CD28 expression.