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Biomedical subjects

A Singer

Publications and source records attributed to A Singer.

At least 217 records · Page 12Linked to original sources
PubMed1988

Engagement of the CD4 molecule influences cell surface expression of the T-cell receptor on thymocytes.

The intrathymic differentiation process by which precursor cells derived from the bone marrow develop into immuno-competent T lymphocytes is poorly understood. Most thymocytes express both CD4 and CD8 accessory molecules, yet little is known about either the function of these molecules or the responsiveness of the CD4+8+ double positive thymocytes that bear them. Here, we address the possibility that CD4 engagement influences T-cell receptor (TCR) expression on developing thymocytes. We engaged CD4 molecules on murine thymocytes by in vivo injection of an anti-CD4 monoclonal antibody, which reduced the surface expression of CD4 on CD4+ thymocytes. More importantly, CD4 engagement also affected TCR expression on CD4+ thymocytes, but the effect on CD4+8+ double positive and CD4+8- single positive thymocytes was very different. CD4+8+ thymocytes responded to CD4 engagement by dramatically increasing surface expression of TCR, whereas CD4+8- thymocytes decreased surface expression of TCR. These results demonstrate that the effect of CD4 engagement on TCR expression is dependent upon the developmental state of the responding thymocyte, and, most interestingly, results in increased TCR expression by double positive thymocytes.

Animals↗
PubMed1988

Effect of cigarette smoking on cervical epithelial immunity: a mechanism for neoplastic change?

Langerhans' cells in cervical epithelium in colposcopic biopsy specimens were identified by immunocytochemical staining for S100 protein and T6 (CD1) antigen, and their density was quantified. Possible cofactors for the development of cervical neoplasia were examined for any effect on the cell counts per unit area. Current cigarette smoking was associated with a significant decrease in the Langerhans' cell population in both normal epithelium and lesions due to cervical intraepithelial neoplasia. Ex-smokers tended to have cell counts between those of smokers and non-smokers. There was a dose-response relation between number of cigarettes smoked daily and effect on cell counts. These findings of a local immunological effect of smoking on cervical epithelium may explain the means by which cigarette smoking contributes to the development of cervical neoplasia.

Cell Count↗
PubMed1988

IL-1 as a co-factor for lymphokine-secreting CD8+ murine T cells.

Immunologically important among the known biologic activities of IL-1 is its ability to function as a co-factor for responses mediated by lymphokine secreting CD4+ Th cells. In contrast to its known effects in CD4+ T cell responses, IL-1 is not known to play a role in CD8+ T cell responses. In the present study, we have assessed the ability of murine recombinant IL-1 to function as a co-factor for stimulating CD8+ T cells to secrete lymphokines such as IL-2. We found that, in conjunction with either Ag or mitogen, IL-1 is able to stimulate lymphokine-secreting CD8+ T cells. Furthermore, we found that, as a consequence of its stimulation of lymphokine-secreting CD8+ T cells, IL-1 is able to reconstitute MHC class I allospecific cytolytic T lymphocyte responses by cell populations depleted of both accessory cells and CD4+ T cells. These results demonstrate that the biologic activity of IL-1 is not restricted to CD4+ cell responses, and suggests that IL-1 can function as a co-factor for the stimulation of lymphokine-secreting Th cells regardless of their CD4/CD8 phenotype. If IL1 acts directly on lymphokine-secreting T cells or on the APC with which they interact is not yet certain.

Animals↗
PubMed1988

Evidence for involvement of dual-function T cells in rejection of MHC class I disparate skin grafts. Assessment of MHC class I alloantigens as in vivo helper determinants.

The present study further characterizes the cellular mechanisms involved in the in vivo rejection of MHC class I-disparate skin allografts. Previously, we demonstrated that class I-specific rejection responses could result from collaborations between distinct populations of lymphokine-secreting T helper (Th) and lymphokine-responsive T effector (Teff) cells. In the present study, we have assessed the possibility that class I-specific rejection responses could also result from a second cellular mechanism involving a single population of dual-function Th/Teff cells that would not have any further requirement for cell-cell collaboration. Our experimental strategy was to determine the ability of MHC class I-allospecific T cells, in response to class I allodeterminants expressed on skin grafts, to provide help in vivo for activation of helper-dependent Teff cells. We found that class I anti-Kbm1-allospecific T cells would reject bm1 skin allografts, but would not generate help for the activation of helper-dependent effector cells that were specific for third-party skin allografts (e.g., grafts expressing Kbm6, Qa1a, or H-Y allodeterminants). This failure of anti-Kbm1 T cells to provide help in response to bm1 skin allografts was not due to an inability of lymphokine-secreting anti-Kbm1 Th cells to recognize and respond in vivo to Kbm1 allodeterminants expressed on skin, since lymphokine-secreting anti-Kbm1 Th cells were specifically primed in animals engrafted with bm1 skin allografts. Nor was any evidence found that this failure was due to active suppression of anti-Kbm1 helper activity. Rather, we found that anti-Kbm1 T cells consumed nearly all of the helper factors they secreted. Taken together, these results are most consistent with the in vivo activity of dual-function Th/Teff cells that consume the lymphokines they secrete. Thus, this study demonstrates that MHC class I-disparate skin allografts can be rejected by two mechanisms, depending on the ability of the allospecific Teff cell to secrete helper lymphokines. MHC class I-disparate grafts can be rejected by (a) class I-allospecific Teff cells that are unable to produce lymphokine but are responsive to exogenous T cell help; and (b) class I-allospecific dual-function Th/Teff cells that are able to both produce and consume soluble lymphokine.

Animals↗
PubMed1988

Differentiation of Ia-reactive CD8+ murine T cells does not require Ia engagement. Implications for the role of CD4 and CD8 accessory molecules in T cell differentiation.

The present study was undertaken to assess the Ia differentiation requirements of CD8+ class II-allospecific CTL, whose CD8+ phenotype is apparently "discordant" with their MHC class II reactivity. To do so, we compared the effect of in vivo anti-Ia blockade on the differentiation of Ia-reactive CD8+ CTL with its effect on the differentiation of CD4+ T cells. We found that anti-Ia blockade did not detectably interfere with the differentiation of CD8+ Ia-reactive CTL, even though it arrested the differentiation of CD4+ T cells. Thus, the differentiation of CD4+ T cells is strictly dependent upon Ia engagement, whereas the differentiation of CD8+ T cells, even those with reactivity against MHC class II alloantigens, does not require Ia engagement. These results support the concept that Ia-reactive CD8+ T cells are conventional CD8+ CTL, probably selected by self-class I MHC molecules during differentiation, whose receptors fortuitously crossreact on MHC class II alloantigens. Taken together, the present data indicate an intimate relationship between CD4/CD8 expression with MHC class specificity during T cell differentiation and selection. We suggest that an active triggering role for CD4 and CD8 accessory molecules in T cell differentiation is best able to explain these observations.

Animals↗
PubMed1988

Cell surface expression of the amino-terminal domain of A kappa alpha. Recognition of an isolated MHC antigenic structure by allospecific T cells but not alloantibodies.

To evaluate the relationship between structure and function of the alpha 1 and beta 1 domains of class II MHC molecules, a strategy has been developed whereby isolated alpha 1 or beta 1 domains can be expressed on the surface of transfected mouse L cells as a part of a hybrid class II/class I molecule. The construction and expression of a chimeric class II/class I gene encoding the first two exons of A kappa alpha linked to the C2, TM and cytoplasmic exons of H-2Dd (A kappa alpha 1/DdC2) are described. High levels of A kappa alpha 1/DdC2 protein were detected on transfected L cells with a DdC2-specific mAb. An anti-Ia xenoantiserum specifically bound to A kappa alpha 1/DdC2-transfected L cells, although 12 different mAb reactive against I-A kappa alpha and an anti-Ia kappa alloantiserum did not bind these cells. However, alloreactive Ia kappa-specific CTL lines were able specifically to lyse cells expressing the hybrid A kappa alpha 1/DdC2 molecule. This indicates that the isolated A kappa alpha 1 domain preserves some of the structure of the native molecule and demonstrates the recognition by T cells of domain-specific A alpha allodeterminants.

Animals↗
PubMed1988

Intrathymic differentiation and tolerance induction of lymphokine-secreting Lyt-2+ T helper cells.

The present study has assessed thymic influence on the differentiation and recognition specificity of developing Lyt-2+ lymphokine-secreting T cells, and compared it with those of developing Lyt-2+ CTL. It was demonstrated that development of Lyt-2+ lymphokine-secreting Th cells requires an intrathymic differentiation step, and that peripheral Lyt-2+ lymphokine-secreting Th cells, unlike peripheral Lyt-2+ CTL, are profoundly tolerant to intrathymically expressed alloantigens. These data are interpreted as demonstrating that functionally distinct Lyt-2+ T cell populations are heterogeneous in their requirements for differentiation and/or activation.

Animals↗
PubMed1988

Analysis of two distinct B cell activation pathways mediated by a monoclonal T helper cell. II. T helper cell secretion of interleukin 4 selectively inhibits antigen-specific B cell activation by cognate, but not noncognate, interactions with T cells.

A single monoclonal T helper (Th) clone can activate B cells in two distinct pathways; a cognate pathway requiring a major histocompatibility complex (MHC)-restricted T-B cell interaction, and a noncognate pathway not requiring an MHC-restricted T-B cell interaction. The present study was undertaken to investigate whether Th cells mediating a given immune response provide further regulatory function to B cells other than helper function. It was demonstrated that conditions of high antigen concentration which activate a noncognate B cell activation pathway simultaneously inhibit IgG responses. The inhibition is shown to be mediated by the T cell factor interleukin 4, produced by activated cloned Th cells. The inhibitory effect of this factor is directed to B cells and is MHC-unrestricted, antigen-nonspecific, and IgG class-specific. In addition to being susceptible to the effects of augmenting cells and suppressor cells, cloned Th cell populations can therefore themselves function as regulatory cells to inhibit IgG responses when stimulated with high dose of specific antigen. These results indicate that Th cells function to regulate B cells both positively and negatively, depending upon the activation conditions.

Animals↗
PubMed1988

Evidence that the effector mechanism of skin allograft rejection is antigen-specific.

In vivo rejection responses are initiated by specific T-cell recognition of foreign histocompatibility antigens expressed by tissue allografts, but it is not certain if the effector mechanism mediating the actual tissue injury is also antigen-specific. To directly assess the specificity of the effector phase of in vivo rejection responses, we constructed B6 in equilibrium with A/J allophenic mice that are genetic mosaics whose individual cells express either H-2b or H-2a histocompatibility antigens but not both. Trunk skin from B6 in equilibrium with A/J allophenic mice was grafted onto immunoincompetent H-2b nude mice and allowed to heal and regrow hair that was both black and white, reflecting the genetic mosaicism of the allophenic grafts. One month after engraftment, the H-2b nude animals were reconstituted with syngeneic H-2b T cells reactive against H-2a allodeterminants. An obvious rejection response ensued involving antigen-nonspecific inflammatory destruction of the epidermis and complete hair loss. Despite the intensity of the nonspecific inflammatory response, the allophenic skin grafts survived. Importantly, the allophenic grafts regrew hair and the predominant color of that hair was black, providing visual proof that syngeneic B6 melanocytes and hair follicle cells had not been destroyed. Thus, these results demonstrate that although the intense inflammatory component of skin graft rejection responses is capable of damaging superficial epidermal cells nonspecifically, it does not cause rejection of skin allografts. Rather, rejection of skin allografts is mediated by antigen-specific effector T cells that assess individual cells within the dermis of the graft for expression of foreign histocompatibility antigens.

Animals↗
PubMed1988

Nonequivalent effects of PKC activation by PMA on murine CD4 and CD8 cell-surface expression.

The membrane glycoproteins CD4 (L3T4) and CD8 (Lyt2) are expressed on distinct populations of mature murine T lymphocytes, and are thought to be receptors for monomorphic determinants expressed on MHC class II and class I molecules, respectively. Although they differ in their ligand specificity, it has been presumed that CD4 and CD8 perform equivalent functions in the T cells that bear them. Since activation of protein kinase C (PKC) is known to cause rapid down-regulation of various receptors, including the T cell receptor complex (TcR complex), we treated cells with phorbol 12-myristate 13-acetate (PMA), a PKC activator, to determine whether cell-surface expression of CD4 and CD8 would be similarly affected by this intracellular mediator. Brief or relatively prolonged treatment with PMA induced mature murine T cells to reduce their surface expression of the TcR complex and of CD4, but not of CD8. Similarly, PMA rapidly induced transfected L cells to down-regulate surface CD4 expression, but had no effect on surface CD8 expression. Most significantly, PMA treatment induced CD4+CD8+ immature thymocytes to rapidly reduce their surface CD4 expression, but, again, it had no immediate effect on the surface expression of CD8. These results indicate that CD4 and TcR complex cell-surface expression are both sensitive to PKC activation by brief treatment with PMA, whereas CD8 expression is not, and suggest that CD4 and CD8 surface expression levels are regulated by distinct intracellular mechanisms.

Animals↗
PubMed1988

Psychosexual trauma of an abnormal cervical smear.

The psychosexual sequelae of diagnosis and treatment of pre-invasive cervical atypia were assessed in three groups of women. The first group included 30 women referred to a colposcopy clinic with an abnormal cervical smear indicating cervical intraepithelial neoplasia (CIN), the second comprised 50 women who were traced as sexual partners of men with penile human papillomavirus (HPV) infection; 26 of them had histologically proven cervical atypia and 24 had no such evidence. The third group included 25 women traced as partners of men with non-specific urethritis and who did not have cervical disease. Before and after questionnaires assessed six aspects of sexual behaviour and responses before diagnosis and 6 months after treatment in women with cervical atypia. These were compared with answers given by women investigated and treated, if necessary, as partners of men with sexually transmitted disease (control group). There were statistically significant adverse psychosexual sequelae associated with diagnosis and treatment of pre-invasive cervical epithelial disease.

Adult↗
PubMed1988

Subclinical penile human papillomavirus infection and dysplasia in consorts of women with cervical neoplasia.

Fifty men whose sexual partners were 50 women with histologically proved cervical intraepithelial neoplasia (CIN) grade III (severe dysplasia or carcinoma in situ) were studied. A further 25 men whose current regular sexual partners were 25 women with chlamydial cervicitis were recruited as controls. If either of the partners in either group had genital condylomata acuminata or a known history of similar lesions, the couple was excluded from the study. Abnormal penile epithelium, which was detected by colposcopy after application of 5% acetic acid to the penile skin, was reported in 25 men in the study group compared with three in the control group. Histologically proved subclinical penile infection with human papillomavirus (HPV) was present in 23 men in the study group compared with three in the control group (p less than 0.01). Of the 50 men in the study group, four had histologically proved severe penile dysplasia or carcinoma in situ with evidence of HPV infection, the disease being subclinical in each case and diagnosed on histology of a specimen obtained by colposcopically directed biopsy. HPV DNA was detected on filter hybridisation of penile scrapes from 15 of the 23 men in the study group with histologically proved penile HPV infection, HPV16 DNA being detected in 10 of them. HPV DNA was detected on DNA-DNA hybridisation of biopsy material in seven of 18 men with histologically proved penile HPV infection. Five of these biopsy specimens were positive for HPV16 DNA. Only one man in the control group had HPV DNA detected in a penile scrape. This patient had histologically proved subclinical penile HPV infection. Such lesions may represent an important male reservoir of HPV types implicated in genital squamous carcinogenesis in both sexes.

Adult↗
PubMed1988

Immune mechanisms of tissue destruction in vivo.

In vivo rejection responses are initiated by specific T cell recognition of foreign histocompatibility antigens expressed by tissue allografts, but it is not certain if the effector mechanism mediating the actual tissue injury is also antigen specific. To directly assess the specificity of the effector phase of in vivo rejection responses, we constructed B6 less than----greater than A/J allophenic mice which are genetic mosaics whose individual cells express either H-2b or H-2a histocompatibility antigens, but not both. Trunk skin from B6 less than----greater than A/J allophenic mice was grafted onto immunoincompetent H-2b nude mice and allowed to heal and regrow hair that was both black and white, reflecting the genetic mosaicism of the allophenic grafts. One month after engraftment, the H-2b nude animals were reconstituted with syngeneic H-2b T cells reactive against H-2a allodeterminants. An obvious rejection response ensued involving antigen-nonspecific inflammatory destruction of the epidermis and complete hair loss. Despite the intensity of the nonspecific inflammatory response, the allophenic skin grafts survived Importantly, the allophenic grafts regrew hair and the predominant color of that hair was black, providing visual proof that syngeneic B6 melanocytes and hair follicle cells had not been destroyed. Thus, destruction of skin allografts is mediated by antigen specific effector T cells that assess individual cells within the dermis of the graft for expression of foreign histocompatibility antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗