A functional idiotypic network of T helper cells and antibodies, limited to the compartment of “naturally” activated lymphocytes in normal mice

Abstract

As shown previously, idiotype (Id) sharing between anti-2,4,6-trinitrophenyl T helper (Th) cells and antibodies in BALB/c mice results from immunoglobulin (Ig)-dependent selection of the T cell repertoire. In contrast, a clonotype defined by the same F6(51) anti-Id antibody is expressed by C57BL/6 anti-(4-hydroxy-3-nitrophenyl)acetyl Th cells independently of Ig influences. We have now used these systems to test the hypothesis that Ig-dependent Th cell repertoire selection occurs in the compartment of "naturally" activated lymphocytes. "Naturally" activated or resting splenic L3T4+ cells were separated from normal BALB/c and C57BL/6 mice and tested, either directly or after in vitro priming, in hapten-specific helper assays for expression of the clonotope defined by the F6(51) anti-Id antibody. The results show the selective expression of the antibody-dependent T cell Id in the "naturally" activated helper cell compartment. In contrast, when the T cell Id is expressed in the absence of Ig-dependent selection, it is only detected in the resting helper cell repertoire. Furthermore, BALB/c "natural" IgM antibodies with anti-Id specificities similar to F6(51) show functionally relevant interactions with syngeneic "naturally" activated Th cells. These are also characterized by high paratopic/Id degeneracy, as compared to helper cells obtained by conventional immunization. These results demonstrate repertoire differences between the set of (resting) lymphocytes participating in immune responses, vs. those "internally" activated in normal individuals. They also suggest the importance of Id network interactions in the compartment of "naturally" activated T and B cells.

Transplantation tolerance correlates with high levels of T- and B-lymphocyte activity.

“…Thus, a distinctive feature of internally activated B and T cells in normal mice appears to be a high degree of idiotypic connectivity involving B cells plus antibodies and T-cell receptors (35,36). This functional idiotypic network is established early in life (37)(38)(39), maintained by continuous mutual selection (40) and positively selecting autoreactive clones, particularly those producing autoantibodies (41,42), as in transplantation tolerance (43). We can then consider that neonatally induced transplantation tolerance is established by the complementation of host and donor functional networks and maintained by self-referential lymphoid activity.…”

Genetic control of natural antibody repertoires: I. IgH, MHC and TCRβ loci

“…This contention was directly supported by a second set of experiments that unravelled serum IgM repertoire differences across TCR g -congenic mice. Selective interactions between antibody repertoires and T cells in normal animals have been reported by several groups in the past (reviewed in [31]), and shown to be limited to the compartment of naturally activated T and B lymphocytes [32][33][34]. Unfortunately, these experiments were conducted at a time when appropriate molecular analysis could not be carried out.…”

Evidence for a functional idiotypic network among natural antibodies in normal mice.

“…Such a functional network does not operate in the small lymphocyte pool, as these cells are resting, and they simply cannot be engaged in functionally relevant interactions. This argument has been developed in some detail (22). In brief, newly produced immunocompetent lymphocytes that find productive internal connections-other lymphocyte receptors or antibodies, or other molecular patterns in the internal milieu-are activated into the large-cell pool, becoming, together with their complementarities, members of a functional network.…”