T cell expression of class II MHC/peptide complexes may be important for maintenance of peripheral self-tolerance, but mechanisms underlying the genesis of class II MHC glycoproteins on T cells are not well resolved. T cell APC (T-APC) used herein were transformed IL-2-dependent clones that constitutively synthesized class II MHC glycoproteins. When pulsed with myelin basic protein (MBP) and injected into Lewis rats, these T-APC reduced the severity of experimental autoimmune encephalomyelitis, whereas unpulsed T-APC were without activity. Normal MBP-reactive clones cultured without APC did not express class II MHC even when activated with mitogens and exposed to IFN-γ. However, during a 4-h culture with T-APC or macrophage APC, recognition of MBP or mitogenic activation of responder T cells elicited high levels of I-A and I-E expression on responders. Acquisition of class II MHC glycoproteins by responders was resistant to the protein synthesis inhibitor cycloheximide, coincided with transfer of a PKH26 lipophilic dye from APC to responders, and resulted in the expression of syngeneic and allogeneic MHC glycoproteins on responders. Unlike rested I-A− T cell clones, rat thymic and splenic T cells expressed readily detectable levels of class II MHC glycoproteins. When preactivated with mitogens, naive T cells acquired APC-derived MHC class II molecules and other membrane-associated proteins when cultured with xenogeneic APC in the absence of Ag. In conclusion, this study provides evidence that APC donate membrane-bound peptide/MHC complexes to Ag-specific T cell responders by a mechanism associated with the induction of tolerance.

Significance: Inflammation is involved in the pathogenesis of many chronic diseases. Many deleterious effects of inflammation are mediated through increased production of proinflammatory mediators, known as cytokines and chemokines. Many current therapies for these diseases involve blocking single proinflammatory mediators, such as TNF, using parenteral administration of recombinant binding proteins. We demonstrate here that a genetic modification in the mouse that increases the expression of an endogenous antiinflammatory protein, tristetraprolin (TTP), results in protection against mouse models for several human inflammatory diseases, including rheumatoid arthritis, psoriasis, and multiple sclerosis, presumably by decreasing the production of proinflammatory cytokines. Our results suggest that increasing TTP expression may be an effective therapeutic strategy in the treatment of certain inflammatory diseases.

Four highly purified synthetic peptides encompassing segments of the 68-86 region [for the numbering system used, see Eylar, E.H., Brostoff, S., Hashim, G., Caccam, J. & Burnett, P. (1971) J. Biol. Chem. 246, 5770-5784] of myelin basic protein (MBP), a region known to induce experimental allergic encephalomyelitis (EAE) in Lewis rats, were used to define and compare structure-function relationships between the primary structure of the 68-86 sequence and the three following biological activities: induction of EAE in Lewis rats, stimulation of T lymphocytes in vitro as measured by augmented cellular transfer of EAE to syngeneic recipients, and lymphocyte proliferation, as measured by [3]thymidine incorporation. Guinea pig (GP) MBP was approximately 60 or 1500 times more active than the GP68-84 (Y G S L P Q K S Q R S Q D E N; single-letter amino acid abbreviations) or the modified bovine (MB) 68-84 (Y G S L P Q K A Q R P Q D E N) peptides for induction of EAE, respectively. Furthermore, lymphocytes primed with either GPMBP, GP68-84, or MB68-84 crossreacted in vitro with either GPMBP, GP68-84, or MB68-84 for activation of lymphocyte transfer activity. In contrast, lymphocytes primed with either GP68-84 or MB68-84 exhibited antigen-specific proliferation in vitro exclusively in response to either GP or MB sequences, respectively. Neither GP75-84 (S Q R S Q D E N) nor GP75-86 (S Q R S Q D E N P V) induced EAE, activated lymphocytes for EAE transfer, or stimulated lymphocyte proliferation under conditions and doses tested. We conclude that (i) structurally distinct determinants, reflecting existence of functionally independent classes of antigen receptors, specify encephalitogenic and proliferative responses of primed lymphocytes and (ii) determinants for EAE induction, cellular transfer of EAE, and lymphocyte proliferation include amino acid residues in the 68-74 (Y G S L P Q K) sequence of GPMBP.