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35. Alterations of T cell activation signalling and cytokine production by postmenopausal estrogen levels

Author

Taylor Douglas D, Nakajima Steven T, Gercel-Taylor Cicek, and Ku Lowell T

Subjects
Immunologic diseases. Allergy, RC581-607, Geriatrics, RC952-954.6
Abstract

Abstract Background Immunosenescence is an age-associated disorder occurring primarily in T cell compartments, including altered subset composition, functions, and activation. In women, evidence implicates diminished estrogen in the postmenopausal period as a contributing factor to diminished T cell responsiveness. Since hypoestrogenism is present in postmenopausal women, our objective focused on whether T cell activation, defined as signalling molecule expressions and activation, and function, identified as IL-2 production, were affected by low estrogen. Methods Using Jurkat 6.1 T cells, consequences of 4 pg/ml (corresponding to postmenopausal levels) or 40 pg/ml (premenopausal levels) of estradiol (E2) were analyzed on signalling proteins, CD3-zeta, JAK2, and JAK3, determined by Western immunoblotting. These consequences were correlated with corresponding gene expressions, quantified by real time-polymerase chain reaction. Tyrosine phosphorylation of CD3-zeta was defined by immunoprecipitation and western immunoblotting following activation by T cell receptor (TcR) cross-linking. CD3-zeta expression and modulation was also confirmed in T cells from pre- and postmenopausal women. To assess functional consequences, IL-2 production, induced by PMA and ionomycin, was determined using enzyme-linked immunosorbent spot assay (ELISpot). Results At 40 pg/ml E2, the level of signalling protein CD3-zeta was elevated 1.57-fold, compared with cells exposed to 4 pg/ml E2. The CD3-zeta proteins also exhibited altered levels of activation-induced phosphorylation in the presence of 40 pg/ml E2 versus 4 pg/ml: 23 kD phosphorylated form increased 2.64-fold and the 21 kD form was elevated 2.95-fold. Examination of kinases associated with activation signalling also demonstrated that, in the presence of 40 pg/ml E2, JAK2 protein expression was increased 1.64-fold (p < 0.001) and JAK3 enhanced 1.79-fold (p < 0.001) compared to 4 pg/ml. mRNA levels for CD3-zeta, JAK2, and JAK3 were significantly increased following exposure to 40 pg/ml E2 (2.39, 2.01, and 2.21 fold, respectively) versus 4 pg/ml. These findings were confirmed in vivo, since T cells from postmenopausal women exhibited 7.2-fold diminished CD3-zeta expression, compared to pre-menopausal controls and this expression was elevated 3.8-fold by addition of 40 pg/ml E2. Functionally, Jurkat cells exposed to 40 pg/ml E2 and activated exhibited significantly elevated numbers of IL-2 producing colonies compared to 4 pg/ml (75.3 ± 2.2 versus 55.7 ± 2.1 colonies, p < 0.0001). Conclusion Jurkat T cells exposed to 4 pg/ml E2 expressed significantly diminished activation signalling proteins, correlating with reduced IL-2 production. Lower signalling protein levels appear to result from decreased CD3-zeta, JAK2, and JAK3 gene expressions. These findings may provide a molecular basis for immunosenescence associated with the postmenopausal state.

Published
2009
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41. Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy

Author

Stern, Robert A., primary, Tripodis, Yorghos, additional, Baugh, Christine M., additional, Fritts, Nathan G., additional, Martin, Brett M., additional, Chaisson, Christine, additional, Cantu, Robert C., additional, Joyce, James A., additional, Shah, Sahil, additional, Ikezu, Tsuneya, additional, Zhang, Jing, additional, Gercel-Taylor, Cicek, additional, and Taylor, Douglas D., additional

Published
2016
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47. Exosomal microRNA Signatures in the Diagnosis and Prognosis of Ovarian Cancer

Author

LOUISVILLE UNIV KY SCHOOL OF MEDICINE, Taylor, Douglas D, LOUISVILLE UNIV KY SCHOOL OF MEDICINE, and Taylor, Douglas D

Abstract

Our original goal was to correlate exosomal miRNA profiles within circulating tumor-derived exosomes with cancer diagnosis, characterization of circulating tumor-derived vesicles and development of methodology for their specific isolation were essential for specific analyses of tumor-derived exosomal cargoes. Our discovery of exosomal microRNA in cancer patients focused on miRNAs, previously demonstrated in tumor biopsies or ovarian tumor cells. We have observed that while some miRNAs that are up-regulated with the tumor or also up-regulated in their exosomes, some tumor-up-regulated miRNAs are not up-regulated within exosomes. Further, certain miRNAs down-regulated within the tumor are up-regulated in exosomes. We demonstrate that miRNA signatures derived from ovarian tumor exosomes exhibit some miRNAs that are undetectable within the tumor. These findings demonstrate the highly selective nature of miRNA packaging. Although the exosomal miRNA signatures for ovarian cancer patients appear to be similar regardless of stage, significant differences among early (Stage I and II) and late stage (Stage III) ovarian cancer were demonstrated: increase expression level and elevated expression of three specific miRNAs within exosomes. Exosomes from ovarian cancer patients were demonstrated to possess elevated levels of RNA, including the presence of specific long-noncoding RNA., The original document contains color images.

Published
2013

48. Identification of Immunoreactive Tumour Antigens Using Free and Exosome-Associated Humoral Responses

Author

Roberson, Carolyn D., Gercel-Taylor, Cicek, Qi, Ying, Schey, Kevin L., Taylor, Douglas D., Roberson, Carolyn D., Gercel-Taylor, Cicek, Qi, Ying, Schey, Kevin L., and Taylor, Douglas D.

Abstract

Altered tumour antigens can initiate cellular and humoral immune responses; however, they often fail to eliminate tumours. In humans, the presence of cancer is generally associated with the suppression of T cell activation and effector responses, characterized as a Th1 to Th2 biased response. This Th2 response leads to the production of tumour-reactive antibodies. Further, neoplastic lesions and biological fluids of cancer patients contain an abundance of tumour-derived exosomes (TDE) expressing tumour antigens. Expression of tumour antigens on TDE may represent an antibody target and serve to block antibody binding to the tumour, implicating a role for these nanovesicles in tumour survival. In this study, ovarian tumour cell proteins were separated by two-dimensional electrophoresis (2-DE) and patient-derived antibodies were used to analyse immunoreactivity. Common immunoreactive proteins among ovarian cancer patients were identified by mass spectrometry and six proteins were selected based on recognition and correlation with cancer pathogenesis. The identity of these proteins were confirmed by immunoreactivity of patient-derived antibodies with recombinant proteins and their presence on in vivo and in vitro-derived ovarian tumour exosomes was defined. Analysis of the TDE demonstrated bound tumour-reactive immunoglobulins, exhibiting immunoreactivity with specific antigens, suggesting that patient-derived antibodies recognize tumour antigens on circulating exosomes.

Published
2013

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