Antigen-experienced T cells undergo a transient phase of unresponsiveness following optimal stimulation.

Interaction of the Ag-specific receptor of T lymphocytes with its Ag/MHC ligand can lead either to cell activation or to a state of unresponsiveness often referred to as anergy. It has been generally assumed that anergy develops as a consequence of inadequate stimulation, such as in response to altered peptide ligands or to agonists presented by costimulatory-deficient accessory cells. The present study uncovers an alternative way of inducing an unresponsive state in T cells. Indeed, we demonstrate herein that Ag-stimulation of murine CD4+ Th clones induces cellular activation, characterized by cytokine production and cell proliferation, followed by a state of transient (lasting up to 6 days) unresponsiveness to further antigenic stimulation. This state of activation-induced unresponsiveness 1) is not a consequence of inadequate costimulation, as it occurs when cells are stimulated in the presence of dendritic cells or anti-CD28 Abs; 2) develops after an optimal response to Ag; 3) is not due to cell death/apoptosis or CTLA-4 engagement; 4) down-regulates the proliferation and cytokine production of both Th1- and Th2-like clones; and 5) does not affect the early steps of signal transduction. Finally, naive T cells are not sensitive to this novel form of unresponsiveness, but become gradually susceptible to activation-induced unresponsiveness upon Ag stimulation. Collectively, these data suggest that activation-induced T cell unresponsiveness may represent a regulatory mechanism limiting the clonal expansion and effector cell function of Ag-experienced T cells, thus contributing to the homeostasis of an immune response.

Low responsiveness to immunization with immunoglobulin E/antigen and immunoglobulin G/antigen complexes in H-2Ab mice.

Immunoglobulin (Ig)E and IgG antibodies specific for 2,4, 6-trinitrophenyl (TNP) are able to enhance the carrier-specific antibody response to TNP-conjugated soluble proteins such as bovine serum albumin (BSA). We have recently reported that mice carrying the MHC class II Ab molecule are low responders to immunization with IgE/antigen complexes and now show that H-2Ab mice are also low responders to IgG/antigen complexes. In addition, we found that spleen cells from naive low- and high-responder mice captured IgE/antigen complexes exclusively on B cells, and that the binding was completely inhibited by monoclonal antibodies (MoAbs) against the low-affinity receptor for IgE (FcepsilonRII or CD23). The IgG/antigen complexes were targeted both to B cells and macrophages. The binding of IgG/antigen to B cells primarily seemed to be dependent on the low-affinity receptor for IgG (FcgammaRII or CD32), although some influence of complement receptor 2 (CR2 or CD21) was seen. Capture of IgG/antigen complexes on macrophages was partially blocked by MoAbs against FcgammaRII/III. There was no difference in expression of FcepsilonRII, FcgammaRII/III, CR1, CR2, and CR3 between low- and high-responder strains, thus excluding low levels of these FcRs and CRs as a reason for low responsiveness in H-2Ab mice.

Impaired antibody responses in H-2Ab mice.

In murine in vivo systems, Ags administered in physiologic solutions together with specific IgE induce a significantly higher Ab response than Ags administered alone. In vitro, IgE in complex with Ag enhances B cell-mediated presentation of the Ag to T cells. Both phenomena require an intact low affinity receptor for IgE (Fc epsilon RII/CD23), suggesting that the effect on in vivo Ab responses is caused by increased Ag presentation. We here show that mice carrying the MHC class II Ab molecule (e.g., C57BL/6 and 129/Sv) do not produce Abs to BSA when immunized with BSA-2,4,6-trinitrophenyl (TNP) in complex with monoclonal IgE anti-TNP. In contrast, strains of all other MHC haplotypes tested (H-2d, H-2k, H-2p, H-2q, and H-2s) respond vigorously to IgE/BSA-TNP complexes, with Ab responses several hundred-fold higher than the responses in H-2b mice. C57BL/6 mice were unable to produce a carrier-specific response also after immunization with IgE/OVA-TNP, IgE/diphtheria toxoid-TNP, or IgE/tetanus toxoid-TNP. Although the low responsiveness mapped to the Ab region, responsiveness was not restored in C57BL/6 mice carrying transgenic Ak, suggesting that a nonclassical A-region-encoded gene product is involved. Most importantly, our data call attention to the fact that the C57BL/6 and 129 mouse strains, which are widely used for producing transgenic animals, have defective immune responses.