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P Matzinger

Publications and source records attributed to P Matzinger.

At least 19 recordsLinked to original sources
PubMed1996

Long-lasting CD8 T cell memory in the absence of CD4 T cells or B cells.

The cellular basis of immunological memory has been a debated issue. It is not clear whether CD8 T cell memory is maintained by long-lived cells or by specific or nonspecific restimulation. Here, we have approached the question from a different angle, asking whether the cellular interactions that are required to maintain memory are the same as those necessary to activate cytotoxic T lymphocytes. We studied the CD8 memory response to the male antigen H-Y in mice deficient in CD4 cells, or B cells and found that memory in these mice was virtually unimpaired. These results suggest that CD8 memory is CD4 independent and that there is no requirement for long term retention of immune complexes on follicular dendritic cells, nor for B cells as antigen-presenting cells.

Animals↗
PubMed1996

Neonatal tolerance revisited: turning on newborn T cells with dendritic cells.

For some time it has been thought that antigenic challenge in neonatal life is a tolerogenic rather than immunogenic event. Reexamination of the classic neonatal tolerance experiments of Billingham, Brent, and Medawar showed that tolerance is not an intrinsic property of the newborn immune system, but that the nature of the antigen-presenting cell determines whether the outcome is neonatal tolerance or immunization.

Animals↗
PubMed1995

Successful T cell priming in B cell-deficient mice.

B cells are an abundant population of lymphocytes that can efficiently capture, process, and present antigen for recognition by activated or memory T cells. Controversial experiments and arguments exist, however, as to whether B cells are or should be involved in the priming of virgin T cells in vivo. Using B cell-deficient mice, we have studied the role of B cells as antigen-presenting cells in a wide variety of tests, including assays of T cell proliferation and cytokine production in responses to protein antigens, T cell killing to minor and major histocompatibility antigens, skin graft rejection, and the in vitro and in vivo responses to shistosome eggs. We found that B cells are not critical for either CD4 or CD8 T cell priming in any of these systems. This finding lends support to the notion that the priming of T cells is reserved for specialized cells such as dendritic cells and that antigen presentation by B cells serves distinct immunological functions.

Animals↗
PubMed1994

Tolerance, danger, and the extended family.

For many years immunologists have been well served by the viewpoint that the immune system's primary goal is to discriminate between self and non-self. I believe that it is time to change viewpoints and, in this essay, I discuss the possibility that the immune system does not care about self and non-self, that its primary driving force is the need to detect and protect against danger, and that it does not do the job alone, but receives positive and negative communications from an extended network of other bodily tissues.

Animals↗
PubMed1993

Thymus epithelium induces tissue-specific tolerance.

Most current models of T cell development include a positive selection step in the thymus that occurs when T cells interact with thymic epithelium and a negative selection step after encounters with bone marrow-derived cells. We show here that developing T cells are tolerized when they recognize antigens expressed by thymic epithelium, that the tolerance is tissue specific, and that it can occur by deletion of the reactive T cells.

Animals↗
PubMed1992

B cells turn off virgin but not memory T cells.

There are three possible outcomes when a T cell recognizes a cell bearing a self or foreign antigen. (i) The T cell is not sufficiently signaled and is unaffected. (ii) The T cell is activated. (iii) The T cell is turned off. The differentiation state of the T cell is critical to the outcome. Although both virgin and memory T cells can be activated by antigens presented by "professional" antigen-presenting cells such as dendritic cells, they differ in their responses to B cells. Experienced T cells respond to antigen presented by B cells, whereas virgin T cells are rendered tolerant. These findings may relate to the phenomena of low- and high-zone tolerance, neonatal tolerance, and the beneficial effect of blood transfusions on allograft survival.

Animals↗
PubMed1992

A fail-safe mechanism for maintaining self-tolerance.

Using cytotoxic T lymphocyte (CTL) responses to the class I histocompatibility antigen Qa1 and to the minor histocompatibility antigen H-Y, we show that the immune system maintains a peripheral screening process that is able to tolerize a wide variety of potentially autoimmune CTL. The critical factor is the presence or absence of specific T helper cells. If T help is available, CTL precursors that recognize antigen are activated. In the absence of help, they are tolerized. Thus, T helper cells are guardians of peripheral tolerance in CTL.

Animals↗
PubMed1992

Activation events during thymic selection.

During their differentiation in the mouse thymus, CD4+8- cells undergo several of the sequential changes observed upon normal activation of mature, peripheral CD4+ lymphocytes. Expression of CD69, an early activation marker, is first observed on a minority of cells at the T cell receptor (TCR)lo/med double-positive stage, is maximal (50-90%) on heat-stable antigen (HSA)hi TCRhi double-positive, HSAhi TCRmed CD4+8lo, and HSAhi TCRhi CD4+8- cells, and is downmodulated at the mature HSAlo CD4+8- stage. In contrast, CD44, a late activation marker, is selectively expressed at the HSAlo stage. The set of lymphokines that CD4+8- thymocytes can produce upon stimulation also characteristically expands from mainly interleukin 2 (IL-2) at the HSAhi stage, to IL-2 and very large amounts of IL-4, IL-5, IL-10, and interferon gamma (IFN-gamma) at the HSAlo stage. 1 in 30 HSAlo CD4+8- adult thymocytes secrete IL-4 upon stimulation through their TCR. This frequency is 25% of the frequency of IL-2 producers, about 100-fold above that of peripheral (mainly resting) CD4+ T cells. With time after their generation in organ culture, CD4+8- thymocytes lose their capacity to secrete IL-4, IL-5, and IFN-gamma, but not IL-2. Similarly, the frequency of IL-4, but not of IL-2, producers progressively decreases after emigration to the periphery as judged by direct comparison between thymic and splenic CD4+ cells in newborns, or by following the fate of intrathymically labeled CD4+8- cells in adults after their migration to the spleen. This sequence suggests that thymic selection results from an activation process rather than a simple rescue from death at the double-positive stage, and shows that the functional changes induced after intrathymic activation, although transient, are still evident after export to the periphery.

Animals↗
PubMed1991

The JAM test. A simple assay for DNA fragmentation and cell death.

Most current methods for measuring cell death are based on plasma membrane disintegration and the consequent release of cytoplasm. The relevant cells are usually loaded with a label (usually 51Cr or 125I), the release of which is measured. I describe here a method, based on the recent evidence that dying cells often degrade their DNA into small fragments, which measures the DNA retained by living cells rather than the cellular components lost by dying cells. The assay is set up essentially like the current cell lysis assays and harvested like a cell proliferation assay. It is faster, more sensitive, easier to set up, less expensive and safer than the current standard 51Cr release assay.

Animals↗
PubMed1991

T cell memory is short-lived in the absence of antigen.

Immunological memory has generally been ascribed to the development of long-lived memory cells that can persist for years in the absence of renewed antigenic encounter. In the experiments reported here, we have adoptively transferred memory T cells in the presence and absence of priming antigen and assessed their functional survival. The results indicate that, in contrast to the traditional view, the maintenance of T cell memory requires the presence of antigen, suggesting that memory, like tolerance, is an antigen-dependent process rather than an antigen-independent state.

Animals↗
PubMed1991

Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells.

V gamma 9/V delta 2 cells represent a fraction of human gamma/delta cells that is expanded after birth in the periphery, carries markers of activated cells, and becomes a major population in peripheral blood. We found that these cells do not comprise a single population but actually represent two nested sets, the smaller of which, specific for Mycobacterium tuberculosis-pulsed antigen-presenting cells (APC), is contained in a larger set specific for an antigen found on the Molt-4 lymphoma. The larger set, representing 40-80% of all blood gamma/delta cells, is comprised of cells bearing the V gamma 9/C gamma 1 chain. Cells in the smaller, included set have an additional requirement for V delta 2 (and probably for certain permissive junctional regions, since a very small percentage of V gamma 9/V delta 2 cells do not react against mycobacteria-pulsed APC). Optimal stimulation by mycobacteria is dependent on the presence of APC, and is not restricted by classical major histocompatibility complex molecules. Some of the V gamma 9/V delta 2 mycobacteria-specific clones are also stimulated by APC pulsed with different bacteria, such as Listeria monocytogenes and Escherichia coli, indicating that the population includes several different patterns of reactivity. These data establish a relationship in humans between specificity and V gamma/V delta gene usage, and offer an explanation for the peripheral expansion of these gamma/delta cells.

Antigen-Presenting Cells↗
PubMed1989

Does T-cell tolerance require a dedicated antigen-presenting cell?

Almost 30 years ago Burnet proposed that the immune system maintained self-tolerance by deleting autoreactive lymphocytes. Recently it has become clear that for T cells this step occurs in the thymus, where developing T cells first express their antigen-specific receptors. Here a T-cell which encounters its antigen disappears--if it is not dead, it at least stops expressing its receptors. In the periphery by contrast, encounter with antigen leads to activation and proliferation of the responding T-cell. There are two possible explanations for this difference. Either the antigen-presenting cells in the thymus are different from those in the periphery and instead of producing positive signals they directly or indirectly kill the thymocytes; or the T cells themselves are different, and like immature B cells, may die after encounter with antigen. We tested the first possibility and found that dendritic cells from spleen, which are the most potent activators of mature T cells, are also the most potent inactivators of young developing T cells. Thus it is not the antigen-presenting cell which determines whether a T-cell responds or dies, but the T-cell itself or its thymic environment.

Animals↗
PubMed1989

Peripheral tolerance mechanisms prevent the development of autoreactive T cells in chimeras grafted with two minor incompatible thymuses.

The thymus has been shown to play an important role in the generation of T cell tolerance to self antigens. Developing T cells are readily tolerized to antigens which are expressed in the thymus, and it is generally thought that such thymic tolerance occurs by a mechanism of clonal deletion. We sought to examine whether T cells which initially encountered a "self antigen" post-thymically would be rendered tolerant of that antigen, and if so whether the mechanism of tolerance induction would differ from that found for thymic antigens. We constructed bone marrow radiation chimeras which were grafted with two thymus lobes differing in minor histocompatibility antigens. T cells which matured in one thymus would be tolerized to the minor histocompatibility antigens expressed in that thymus but would not encounter, and would therefore have no early opportunity of being tolerized to the minor histocompatibility antigens expressed by the other thymus. The initial encounter with the minor antigens on the second thymus would occur post-thymically. Would these T cells be tolerant or responsive to those minor histocompatibility antigens? We found that tolerance was dominant in these chimeras. The data further suggest that the mechanism responsible for tolerance induction in the periphery may differ from that which operates in the thymus.

Animals↗
PubMed1989

Gamma/delta T cells express a unique surface molecule appearing late during thymic development.

The vast majority of T cells in man and mouse use the alpha/beta form of T cell receptor (TcR), and express either CD4 or CD8, whereas the small subset of gamma/delta T cells are usually CD4-CD8-. In contrast to man and mouse, the gamma/delta subset in sheep, defined here using an anti-gamma/delta monoclonal antibody (mAb), comprises 30%-60% of T cells. We show that gamma/delta T cells in sheep express a unique surface molecule termed T19 which is 215 kDa in size and unrelated to either CD45 or the TcR. The T19 molecule was expressed at a distinct stage during gamma/delta T cell ontogeny within the thymus, since gamma/delta thymocytes which appeared early in fetal ontogeny were T19- and also major histocompatibility complex (MHC) class I- and localized almost exclusively to the outer cortex and cortex of the thymus. "Mature-type" gamma/delta thymocytes which emerged late in thymic development were T19+ and MHC class I+ and localized predominantly to the thymic medulla. The sequence of events indicated that these cells were most likely derived from the early gamma/delta thymocytes. These medullary gamma/delta thymocytes showed a very distinctive association with Hassall's corpuscles, suggesting a role for these structures in gamma/delta thymocyte maturation. In the periphery, T19 was expressed exclusively within the gamma/delta T cell subset, however some gamma/delta T cells were T19-. In particular, a large proportion of gamma/delta T cells within intestinal epithelium lacked T19, indicating a correlation between T19 expression and either function or homing patterns of gamma/delta T cells. Both T19+ and T19- gamma/delta T cells were CD2-, and expressed low levels of LFA-1 and CD5. In addition, gamma/delta T cells recirculated differently from other T cells, and appeared not to enter mesenteric lymph nodes at all from the blood. We propose that T19 is a maturation marker for gamma/delta T cells. In addition, the exclusive expression of T19 by gamma/delta T cells indicates that this molecule most likely serves a fundamental role in the interactions and function of gamma/delta T cells.

Animals↗
PubMed1988

Unresponsiveness to a foreign antigen can be caused by self-tolerance.

In mice, two sets of genes govern the immune response to the synthetic antigen GT. One maps to the major histocompatibility complex and behaves like a typical immune response gene. The second is a background gene encoding a cell surface structure found on B cells. Mice which express, and are therefore tolerant of, one form of this structure do not respond to GT. Thus, tolerance of self generates holes in the T-cell repertoire, partially crippling the immune system.

Animals↗