On the role of regulatory T cells and microbial products in the control of T and B cell immune responses

Self-nonself discrimination is the basic property of the immune system that
allows rejection of pathogens without attacking self-specific structures.
Discrimination of self and nonself is based on both structural features of the antigen
as well as on the context, in which the antigen is encountered. While specific
recognition of nonself-antigens in presence of microbial products induces potent
immune responses, several suppressing mechanisms exist that limit immune reactions
to specifically recognized antigens in a context devoid of microbial agents.
A prominent example of suppressing mechanisms is regulation of T cell
responses by regulatory T cells (Tregs). Treg-mediated suppression is induced upon T
cell receptor (TCR) stimulation of Tregs and therefore dependent on Treg specificity.
We found that TCRs derived from mouse regulatory and conventional T cells cover a
similar spectrum of affinity towards self-antigens, which implies that Tregs express a
similar TCR repertoire as conventional T cells. This result suggests that Tregmediated
suppression is not induced by recognition of self-antigen but rather
regulated by recognition of the immunological context.
Characterization of Treg function in autoimmune diseases is hampered by the
fact that Tregs in an inflamed tissue cannot be discriminated from infiltrating
activated conventional T cells. We report that at the site of autoimmune reactions
Tregs can be distinguished from activated T cells by the expression of CD27. Using
this novel Treg marker we show that the suppressive activity of Tregs isolated from
inflamed tissues is not limited in vitro, which precludes a Treg-intrinsic defect.
However we have observed that cytokines as IL-7 and IL-15, which are present in the
autoimmune inflammatory milieu, potently block Treg-mediated suppression in vitro.
These results suggest that in vivo IL-7 and IL-15 may interfere with Treg function at
the sites of ongoing autoimmune reactions.
Recognition of a context containing signs of microbial invasion leads to the
counterbalancing of suppressing mechanisms and to the induction of potent immune
responses. Such a context is characterized by the presence of pathogen-associated
molecular patterns (PAMPs) that are recognized by Toll-like receptors (TLRs)
expressed on a variety of cell types. We show that TLR triggering is critically
required for the induction of productive T-dependent human naïve B cell responses. B
cell receptor (BCR) triggering and T cell help induced initial B cell proliferation but
were not sufficient to sustain prolonged survival and accumulation of B cells.
Extensive proliferation, isotypic switch and differentiation to Ig-secreting cells were
promoted by microbial agents acting on TLRs expressed by naïve B cells upon BCR
stimulation. This finding demonstrates that humoral immune responses (as cellular
immune responses) are critically dependent on context discrimination via detection of
PAMPs.