Stephan Ehl

Antigen localisation regulates immune responses in a dose‐ and time‐dependent fashion: a geographical view of immune reactivity

Summary: This review summarises experimental evidence to illustrate that induction of immune reactivity depends upon antigen reaching and being available in lymphoid organs in a dose‐ and time‐dependent manner. If antigen reaches lymph organs in a localised staggered manner and with a concentration gradient, a response is induced in the draining lymph node. Antigen‐presenting cells are of critical importance to transport antigen from the periphery to local organised lymphoid tissue. If antigen is all over the lymphoid system, then it deletes all specific cells in the thymus or induces them within a few days: because of their limited life‐span they then die off, leaving the repertoire depleted of this specificity. If antigen does not reach lymphoid organs it is ignored by immune cells. Once a response is induced, activated but not resting T cells will reach antigen outside lymphoid organs, whereas activated B cells differentiate into plasma cells in an inducing environment, mostly in lymphoid tissue including bone marrow, but also in chronic lymphoid‐like infiltrations in peripheral organs. In immunopathology (when the infectious agent is known) or in autoimmunity (when the triggering infectious agent is not known or not recognised) lymphoid tissue may become organised close to the antigen (e.g. in organ‐specific autoimmune diseases) and may thereby maintain an autoantigen‐driven disease‐causing immune response for a long time, The notion that naive T cells get induced or silenced in the periphery may be questioned because induction can only occur in lymphoid organs providing anatomical structures where critical cell‐cell interactions are properly guided and where, therefore, cells are likely to meet sufficiently frequently and in a critical milieu. Since overall immune reactivity critically depends upon the localisation of antigens in a dose‐ and time‐dependent manner, it seems more likely ‐ but this remains to be shown ‐ that activated T cells may get exhausted in non‐lymphoid peripheral tissues, whereas they are usually maintained in lymphoid organs. The critical role of antigen in regulating immune responses also has relevance for our understanding of immunological defence against epithelial and mesenchymal tumours, against many infectious diseases and for understanding autoimmunity and immunological memory. Collectively the data indicate that antigen, impendent upon localisation, dose and time, seems to be the simplest regulator of immune responses.

A comparison of efficacy and specificity of three NK depleting antibodies

This study compares in vivo efficacy and specificity of the three NK cell depleting antibodies anti-asialo GM1, anti-NK 1.1 and the recently described TM beta 1, which is directed against the interleukin-2 receptor beta chain. All three antibodies are equally efficacious as assessed by abolishing NK mediated cytolytic activity induced by a high dose virus infection or Poly IC against YAC-1 targets. Similarly, the generation of virus-specific cytotoxic T cells (CTL) was unimpaired after NK depletion in two different virus infections. However, if mice are treated with the antibodies several days after virus infection, when strong CTL responses have already been generated, anti-asialo GM1 and-to a lesser extent-also TM beta 1 have a significant effect on CTL activity. Only after treatment with anti-NK 1.1 antibody, CTL activity was not significantly impaired. We conclude, that of the NK depleting antibodies currently available, anti-NK 1.1 allows the best differentiation of activated CTL and NK cells in vivo.

Antigen persistence and time of T-cell tolerization determine the efficacyof tolerization protocols for prevention of skin graft rejection

We studied antigen-specific T-cell tolerization therapy using skin transplantation across a defined minor histocompatibility antigen difference. Specific tolerization protocols using short-lived peptide or long-lived spleen cells presenting the peptide as antigen prevented graft rejection without immunosuppression when started before or as long as 10 days after transplantation. Peptide-induced T-cell tolerance was transient, and antigen presentation by the graft was not sufficient to maintain tolerance. In contrast, transfer of antigen-expressing lymphoid cells induced long-lasting tolerance correlating with donor cell chimerism. These findings show that antigen-specific tolerization can induce graft acceptance even when begun after transplantation and that long-term graft survival depends on persistence of the tolerizing antigen.

General and specific immunosuppression caused by antiviral T-cell responses

Summary: Immunosuppression caused by the non‐cytopathic lymphocytic choriomeningltis virus (LCMV) (an RNA virus) is mediated by anti‐viral cytotoxic T cells that destroy LCMV‐infected cells, also of the immune system. While this immunopathological destruction of antigen‐presenting cells, macrophages and follicular dendritic cells and of some CD4+ T cells causes general immunosuppression and impairs immune response to third party antigens, it also enhances exhaustion/deletion of LCMV‐specific CD8+ T‐cell responses. LCMV seems in addition to infect neutralizing antibody‐producing B cells via the specific receptor; immunopathological LCMV‐specific CD8T T‐cell‐mediated elimination of these infected B cells (but not of uninfected internal virus antigen‐specific B cells) causes a highly specific immunosuppression that delays neutralizing antibody responses and thereby enhances virus persistence. Both generalized and specific immunosuppression by CD8+ T‐cell‐mediated immunopathology may be involved in human infections with HIV; hepatitis B virus or hepatitis C virus.

Donor cell persistence and activation-induced unresponsiveness of peripheral CD8 + T cells

We studied the impact of the duration of donor cell persistence on CD8+ T cell responsiveness after adoptive transfer of antigen‐expressing lymphoid cells. Naive or immunized female mice were treated by adoptive transfer of spleen cells from mice ubiquitously expressing a lymphocytic choriomeningitis virus‐derived cytotoxic T lymphocyte (CTL) epitope (gp33u2009–u200941) either alone or in combination with the male H‐Y antigen providing additional antigenic CTL and T helper cell determinants. Low doses of male spleen cells (or sorted B cells) primed CTL, while high doses of the same cells rendered them unresponsive. CTL unresponsiveness induced by high numbers of male spleen cells was dependent upon prolonged persistence of antigen‐expressing donor cells. Unresponsive CTL reverted to a state of activation when the duration of donor cell chimerism was limited. Memory CTL could be rendered unresponsive if antigen‐expressing donor cells were allowed to persist. These results suggest that, irrespective of the type of antigen‐presenting cell and the functional state of the responding T cell, activation and unresponsiveness can represent two different outcomes critically determined by quantitative and kinetic differences of antigen persistence.

Genetic Disorders of Immune Regulation

Immune responses are highly dynamic processes that involve rapid expansion and contraction of immune cell populations, targeted exertion of highly potent effector functions and secretion of soluble mediators that have antimicrobial properties and influence cell functions and interactions. To maintain homeostasis, both innate and adaptive immune responses require tight regulation. Exaggerated inflammatory responses can be the consequence of uncontrolled activation of the immune system and failure to control immune responses against host antigens causes autoimmunity. There are many checkpoints that help to maintain homeostasis in the immune system involving a variety of cells and mediators. It is therefore not surprising that genetic deficiencies in many immunologically relevant molecules can lead to immune dysregulation in addition to but also in the absence of susceptibility to infection.

T-zelluläre und kombinierte Immundefekte

Primare T-zellulare Immundefekte umfassen eine Gruppe seltener Erkrankungen, die Folge genetisch bedingter Storungen der Reifung, Differenzierung und Aktivierung oder der Funktion des T-zellularen Immunsystems sind. Wegen der zentralen immunregulatorischen Funktion der T-Zellen zeigen betroffene Patienten meist auch einen sekundaren B-Zell-Defekt, daher spricht man auch von kombinierten Immundefekten (= das zellulare und humorale System betreffend).