PrefaceThe induction of immunological unresponsiveness by feeding soluble antigens, termed oral tolerance, has been attracting considerable attention as a potential therapy for a variety of systemic inflammatory disorders. However, the physiological role of this phenomenon is in maintaining gastrointestinal homoeostasis and preventing immunopathology in the gut. This review will discuss the mechanisms of oral tolerance in the context of the structure and function of the gut associated lymphoid tissues (GALT), outline how defects in oral tolerance can lead to immunopathology and indicate its therapeutic potential.
We have identified a method of polarizing polyclonal populations of activated T helper cells toward either the Th1 or Th2 phenotype using different short-term in vitro culture conditions. Since the Ag used was an encephalitogenic peptide for SJL/J mice, the pathogenic potential of these cell populations was tested in an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE). Th1 cells reproducibly caused severe EAE, whereas highly polarized Th2 cells did not. Furthermore, highly polarized Th2 cells did not suppress EAE caused by Th1 cells. The anti-inflammatory cytokines made by Th2 cells may simply fail to inhibit tissue destruction mediated by differentiated Th1 cells at the effector phase of the disease. It is also possible that highly polarized Th2 cells may be inefficient at crossing the blood-brain barrier, which may limit their suppressive potential. In contrast, incompletely skewed T cell populations that produced high levels of both Th1 and Th2 cytokines were consistently only weakly encephalitogenic. Therefore, disease inhibition by Th2 cytokines may best be accomplished by intervention at earlier points preceding development of differentiated Th1 cells.
T cell diversity is a key feature of the adaptive immune system. Lymphopenia‐induced proliferation (LIP) can trigger oligoclonal expansion of T cells reacting to foreign or self‐antigens. This can result in loss of T cell diversity and compromise immune fitness that can be achieved following reconstitution by LIP. We demonstrate that CD4+CD25+Fopx3+ regulatory T cells selectively inhibit the spontaneous (fast) form of LIP, which is associated with differentiation into memory/effector‐like cells, and is likely to contain the most reactive T cell clones. Selective suppression of these clones is likely to leave more resources for T cells undergoing the slower homeostatic form of LIP. Putting it all together, we hypothesize that one of the functions of Tregs is to maintain the T cell diversity and overall immune fitness during reconstitution from lymphopenia. We are currently testing this hypothesis directly through flow cytometric analysis of TCR V beta usage, PCR‐based TCR J beta spectratyping, and sampling antigen‐specific cells by means of magnetic bead pull‐down with MHC class I and II tetramers.
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