Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

Abstract

To determine the role that competition plays in a molecular mimic's capacity to induce autoimmunity, we studied the ability of naïve encephalitogenic T cells to expand in response to agonist altered peptide ligands (APLs), some capable of stimulating both self-directed and exclusively APL-specific T cells. Our results show that although the APLs capable of stimulating exclusively APLspecific T cells are able to expand encephalitogenic T cells in vitro, the encephalitogenic repertoire is effectively outcompeted in vivo when the APL is used as the priming immunogen. Competition as a mechanism was supported by: (i) the demonstration of a population of exclusively APL-specific T cells, (ii) an experiment in which an encephalitogenic T cell population was successfully outcompeted by adoptively transferred naïve T cells, and (iii) demonstrating that the elimination of competing T cells bestowed an APL with the ability to expand naïve encephalitogenic T cells in vivo. In total, these experiments support the existence of a reasonably broad T cell repertoire responsive to a molecular mimic (e.g., a microbial agent), of which the exclusively mimic-specific component tends to focus the immune response on the invading pathogen, whereas the rare cross-reactive, potentially autoreactive T cells are often preempted from becoming involved.experimental autoimmune encephalomyelitis | molecular mimicry | multiple sclerosis | driver clones | autoimmune T cell recognition is degenerate; a single T cell can react to a heterogeneous assortment of ligands (1-5). The use of synthetic combinatorial peptide libraries has revealed two key features of this degeneracy: (i) There are a vast number of agonistic ligands for a single clone (possibly >10 6 ) each falling along a spectrum of stimulatory potencies and (ii) the native self determinant is often "suboptimal" when compared with many of the synthetic mimic peptides (4). The concept of molecular mimicry describes a situation in which a foreign microbe can initiate an immune response in which a T or B cell component cross-recognizes self. The amino acid sequence in the mimic determinant and the native self-determinant can be very different and in some instances, apparently chemically unrelated. Although several groups have demonstrated degenerate recognition by autoreactive T cells (1, 6, 7), molecular mimicry as a direct cause of autoimmunity has only rarely been shown (6).We have used the term "driver" to refer to individual selfdirected T cell clones that are required to propagate an autoimmune response. In this paper we ask whether APL-specific, nonself-directed T cells can outcompete naïve driver pathogenic clones for activation. The APLs used in our study can be considered analogous to microbial molecular mimics. The ability of these APLs to induce non-self-directed exclusively APL-specific clones was studied in the myelin basic protein (MBP):Ac1-9-induced B10.PL (H-2 u ) model of experimental autoimmune encephalomyelitis (EAE). EAE is an autoimmune demyelinating disease of the cent...

Jeffamine Derivatized TentaGel Beads and Poly(dimethylsiloxane) Microbead Cassettes for Ultrahigh-Throughput in Situ Releasable Solution-Phase Cell-Based Screening of One-Bead-One-Compound Combinatorial Small Molecule Libraries

“…Since the assay is highly miniaturized, the amount of expensive reagents needed for screening is minimal. In recent years, more investigators are using OBOC method successfully in their research and we expect this trend to continue 3c, 3g, h, 4, 5d, e, 8, 11, 13-14, 22…”

CD4+ virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity

“…In addition, the “sequence rank” of the HEL-specific CDR3 sequence was relatively low in all T cell populations analyzed. Thus, we contend that since the HEL-specific T cells reside at the same low frequency within the “naive” and “memory” compartments, it is highly unlikely that their memory phenotype was a result of a clonal expansion event in response to a molecular mimic [24]. Although a low level of cross-recognition with “self” peptide-MHC complexes could not be excluded, we were unable to detect significant cross-recognition to “self” ML, the mouse analog of HEL (Fig.…”

CD4+T cells in chronic autoantigenic stimulation in MGUS, multiple myeloma and Waldenström's macroglobulinemia

“…Our study also opens the possibility for new therapeutic and even prophylactic strategies, including, among others, appropriately altered peptide ligands (APL) designed to bind with high, but also with reduced affinity to the respective MHC‐II subtypes, recombinant peptide‐analogue/MHC complexes or recombinant Fab fragments specifically recognizing the MHC/peptide complex, all of which are capable of inhibiting specific cognate CD4 + cell help for antigen‐specific B cells in pP‐7 carriers.…”