ANTIGEN LOCALIZATION REGULATES IMMUNE-RESPONSES IN A DOSE-DEPENDENT AND TIME-DEPENDENT FASHION - A GEOGRAPHICAL VIEW OF IMMUNE REACTIVITY

This review summarises experimental evidence to illustrate that induct ion of immune reactivity depends upon antigen reaching and being avail able in lymphoid organs in a dose- and time-dependent manner. If antig en reaches lymph organs in a localised staggered manner and with a con centration gradient, a response is induced in the draining lymph node. Antigen-presenting cells are of critical importance to transport anti gen from the periphery to local organised lymphoid tissue. If antigen is all over the lymphoid system, then ic deletes all specific cells in the thymus or induces them within a few days; because of their limite d hfe-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 bur not resting T cells will reach antigen outside lymphoid organs, whereas activated B cells differentiate into plasma cells in an inducing environment, mos tly in lymphoid tissue including bone marrow, but also in chronic lymp hoid-like infiltrations in peripheral organs. In immunopathology (when the infectious agent is known) or in autoimmunity (when the triggerin g infectious agent is not known or nor recognised) lymphoid tissue may become organised close to the antigen (e.g. in organ-specific autoimm une diseases) and may thereby maintain an autoantigen-driven disease-c ausing immune response for a long time. The notion that naive T cells get induced or silenced in the periphery may be questioned because ind uction can only occur in lymphoid organs providing anatomical structur es 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 u pon 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 a ntigen in regulating immune responses also has relevance for our under standing of immunological defence against epithelial and mesenchymal r umours, against many infectious diseases and for understanding autoimm unity and immunological memory. Collectively the data indicate that an tigen, dependent upon localisation, dose and time, seems to be the sim plest regulator of immune responses.