Polly Matzinger

A conditioned dendritic cell can be a temporal bridge between a CD4 + T-helper and a T-killer cell

To generate an immune response, antigen-specific T-helper and T-killer cells must find each other and, because they cannot detect each others presence, they are brought together by an antigen-loaded dendritic cell that displays antigens to both. This three-cell interaction, however, seems nearly impossible because all three cell types are rare and migratory. Here we provide a potential solution to this conundrum. We found that the three cells need not meet simultaneously but that the helper cell can first engage and ‘condition’ the dendritic cell, which then becomes empowered to stimulate a killer cell. The first step (help) can be bypassed by modulation of the surface molecule CD40, or by viral infection of dendritic cells. These results may explain the longstanding paradoxical observation that responses to some viruses are helper-independent, and they evoke the possibility that dendritic cells may take on different functions in response to different conditioning signals.

Natural adjuvants: Endogenous activators of dendritic cells

Dendritic cells, the most potent antigen-presenting cells, need to be activated before they can function to initiate an immune response. We report here that, in the absence of any foreign substances, dendritic cells can be activated by endogenous signals received from cells that are stressed, virally infected or killed necrotically, but not by healthy cells or those dying apoptotically. Injected in vivo with an antigen, the endogenous activating substances can function as natural adjuvants to stimulate a primary immune response, and they may represent the natural initiators of transplant rejection, spontaneous tumor rejection, and some forms of autoimmunity.

Danger signals: SOS to the immune system

The activation of dendritic cells, necessary for the initiation of primary and secondary immune responses, can be induced by endogenous danger signals - released by tissues undergoing stress, damage or abnormal death - and also by exogenous danger signals elaborated by pathogens. Some endogenous danger signals that recently have been discovered are heat-shock proteins, nucleotides, reactive oxygen intermediates, extracellular-matrix breakdown products, neuromediators and cytokines like the IFNs. We propose that allergy may be initiated by the direct damage of dendritic or other cells by toxic chemicals and allergenic proteases, and suggest that the triggering of danger signal receptors by exogenous pathogen-derived molecules may be more to the advantage of the pathogen than to the host.

Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses

It is currently thought that immune responses are initiated by pathogen-associated molecular patterns or by tissue-derived danger/alarm signals. Here, we propose that these two groups of molecules might not be mutually exclusive. Many of them might be part of an evolutionarily ancient alert system in which the hydrophobic portions of biological molecules act, when exposed, as universal damage-associated molecular patterns to initiate repair, remodelling and immunity.

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.

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.

Gamma chain required for naïve CD4+ T cell survival but not for antigen proliferation.

Lymphoid homeostasis is required to ensure immune responsiveness and to prevent immunodeficiency. As such, the immune system must maintain distinct populations of naïve T cells that are able to respond to new antigens as well as memory T cells specific to those antigens it has already encountered. Though both naïve and memory T cells reside in and traffic through secondary lymphoid organs, there is growing evidence that the two populations may be regulated differently. We show here that naïve T cell survival and memory T cell survival have different requirements for cytokines (including the interleukins IL-2, IL-4, IL-7, IL-9 and IL-15) that use the common cytokine receptor gamma chain (γc). Using monoclonal populations of antigen-specific CD4+ T cells, we found that naïve T cells cannot survive without γc, whereas memory T cells show no such requirement. In contrast, neither naïve nor γc-deficient memory T cells were impaired in their ability to proliferate and produce cytokines in response to in vivo antigenic stimulation. These data call into question the physiological role of γc-dependent cytokines as T cell growth factors and show that naïve and memory CD4+ T cell survival is maintained by distinct mechanisms.

An Innate Sense of Danger

For three quarters of a century, immunologists have based their theories and experiments on the fundamental belief that the immune system discriminates between self and non-self and that, if the system were perfect, it would attack everything that is non-self and be totally tolerant of anything that is self. I have abandoned this belief. Over the years there have accumulated too many immunological findings that don’t fit with and too many questions that are not answered by this paradigm. For example, if each individual’s immune system learns “self” at an early age, then why are new antigens that appear at puberty not considered “foreign” and destroyed. How can normal individuals contain both T and B cells capable of reacting to self antigens like DNA, keratin, and myelin basic protein, yet not have destructive autoimmunity. Why are liver transplants rejected less vigorously than hearts? Why is a newly lactating breast not rejected when it begins to make new proteins? Why is the immune system so bad at dealing with tumors, even when they demonstrably express new, “non-self” antigens? Why do we need adjuvant? Why do we not normally respond to all the foreign antigens in food, to our commensal intestinal bacteria, or to our fetuses or to the sperm that begot them? The answers to these questions are not easily found when we approach the immune system from a self–non-self viewpoint, although they fall easily into place when approached from the perspective that the immune system is more concerned with danger and potential destruction than with the distinction between self and non-self. The danger model is based on the idea that the driving force for the immune system is the need to recognize danger. The model starts with the idea that the immune system defines “danger” as anything that causes tissue stress or destruction. Under this model, antigen-presenting cells are activated by alarm signals from stressed or damaged tissues. Without this activation, no primary immune response can occur. Some of the recent evidence in its favor has been shown and its implications for all of the questions above discussed.

Tissue-based class control: the other side of tolerance

In this Essay, we offer a new perspective on how immune responses are regulated. We do not cover how they are turned on and off, but focus instead on the second major aspect of an immune response: the control of effector class. Although it is generally thought that the class of an immune response is tailored to fit the invading pathogen, we suggest here that it is primarily tailored to fit the tissue in which the response occurs. To this end, we cover such topics as the nature of T helper (TH) cell subsets (current and yet to be discovered), the nature of privileged sites, the difference between oral tolerance and oral vaccination, why the route of immunization matters, whether the TH1-type response is really the immune systems primary defense, and whether there might be a different role for some regulatory T cells.

Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut

Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell–deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.