Regulation of T and B cell responses to chronic antigenic stimulation during Infection, autoimmunity and transplantation

Our immune system has evolved to defend us from pathogens. It does this by making innate responses followed by pathogen-specific Band T-cell responses. The rapidity of these immune responses is quite remarkable; innate responses, of course, occur almost immediately upon pathogen encounter but adaptive responses are also rapidly generated within a week or two even during a primary infection. Naive B and T cells specific for the pathogen are recruited into the response and undergo a program of proliferation and differentiation that results in the generation of helper and effector T cells and the production of antibody from B-cell plasmablasts. The goal of this rapid immune response is to prevent severe disease and mortality from the infection and to eliminate the pathogen. This highly coordinated and powerful effector Tand B-cell response is well suited for dealing with many acute infections. However, not all infections are cleared and there are many examples of persistent infections. Under these conditions of chronic antigenic stimulation, the adaptive immune response to the persisting pathogen becomes highly regulated. A major reason for this inhibition and tuning down of the microbe specific effector response is to avoid excessive immune-mediated damage. The term “exhaustion” is often used to describe this decrease of immune function during chronic infections. Another situation of chronic antigen stimulation is autoimmunity. In this instance, the normal rules of self versus non-self discrimination are broken and the immune response attacks one’s own tissues with severe consequences. But these persistent autoimmune responses are also highly regulated by a variety of mechanisms. Transplantation is also a situation of continued antigen stimulation from the donor tissue, and the host Tand B-cell responses to the mis-matched regions of the donor tissue are controlled by various regulatory mechanisms. The mechanisms that regulate Tand B-cell responses during chronic infections, autoimmunity, and transplantation share common features but also present interesting contrasts because of the different immunological settings. The articles in this volume of Immunological Reviews cover these three areas and address an important topic that is of interest not only from a fundamental understanding of immune regulation but also has clinical implications. Here is a brief synopsis of the articles in this issue, we start with the articles on Transplantation followed by the articles on Autoimmunity and Chronic Infection. The study of tolerance to transplanted organs offers fundamental insight into mechanisms of immunologic non-responsiveness to foreign antigen. These lessons may be distinct from but complementary to data obtained in models of infection, because immune responses to allogeneic tissue are generated in the absence of pathogen-derived molecular patterns (i.e. TLR signaling) and therefore may be more influenced by T-cell costimulatory and coinhibitory signaling and also be more susceptible to suppression by the various regulatory cell subsets. In addition, achieving tolerance is indeed the holy grail of clinical transplantation. As such, ongoing research, as outlined by the articles in this volume, is aimed at identifying cellular and molecular mechanisms that both promote and hinder tolerance induction following transplantation. Bromberg and colleagues begin by addressing the role of lymph node architecture at the crossroads of transplantation tolerance versus immunity. They describe recent findings on the roles of three major LN stromal cell subsets that act as scaffolds to promote transplantation tolerance by presenting tissue antigens to alloreactive CD4+ and CD8+ T cells. Interestingly, these LN stromal cells also The names of the authors are listed alphabetically.