The peripheral T-cell population is educated to recognize a maximum of pathogen-derived epitopes while ignoring self-antigens. As the total number of T-cell clones is limited, each T-cell receptor (TCR) needs to be cross-reactive in order to achieve a wide repertoire. This opens the possibility for T cells to diverge from their defending role and induce auto-aggression by mistake. The factors involved in the initiation of such autoimmune responses remain to be fully understood. In an attempt to assess the role of antigen presenting cells (APC) in the triggering of autoimmunity, we studied the cross-reactivity of TCR transgenic Tg4 T cells, reactive to the Ac1-9 peptide of myelin basic protein (MBP). Using different APC populations and a range of peptide analogues of Ac1-9, we found that the activation of APC enhanced the cross-reactivity of Tg4 cells, and that this effect could be mimicked by resting APC supplemented with exogenous co-stimulation. Further, we observed that the inhibitory effect of an antagonist peptide of the Tg4 TCR was greatly reduced when activated APC were used. However, when co-stimulation was blocked, TCR antagonism was restored to its normal level. Our results show for the first time that the activation of naturally occurring APC, namely dendritic cells, B cells and macrophages, can modulate the reactivity of T cells, both in terms of cross-reactivity and TCR antagonism, and that this effect is most likely due to enhanced levels of co-stimulation.

The use of altered peptide ligands (APL) with TCR antagonist properties holds promise as an antigen-specific therapy for autoimmune disorders. We are investigating the therapeutic potential of APL in experimental autoimmune encephalomyelitis (EAE) using the Ac1-9 peptide of myelin basic protein in H-2u mice. Encephalitogenic T cells recognize Ac1-9 using residues 3Gln and 6Pro as the major TCR contact sites. Use of position 6 APL is compromised by the heterogeneous nature of the Ac1-9-specific repertoire. Here we identify two position 3 APL that act as TCR antagonists on transgenic T cells expressing Ac1-9-specific TCR and that inhibit EAE in H-2u mice. However, the therapeutic capacity of these two APL correlated directly with the ability to maximally inhibit activation of a heterogeneous T cell pool. The implications of these findings for the requirements for EAE induction, the relative contribution of a given T cell subpopulation to pathology and the mechanism underlying EAE inhibition in this model are discussed.

The human immunodeficiency virus type 1 was recently found to use several chemokine receptors in addition to the CD4 molecule for attachment to, and fusion with, CD4+ cells. The interaction between macrophage-tropic HIV-1 strains and one of these chemokine receptors, CCR5, was shown to involve the V3-loop of the viral envelope glycoprotein gp120. Physiological ligands of CCR5, namely the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES, were found to competitively inhibit the V3-loop-CCR5 interaction. We therefore hypothesized that the V3-loop of gp120 of macrophage-tropic HIV-1 may share a binding site on CCR5 with MIP-1alpha, MIP-1beta, and RANTES and that the V3-loop therefore might have some homology with these beta-chemokines. In the present study, we could demonstrate that affinity purified anti-V3-loop antibodies isolated from serum of an HIV-1-infected patient bound to MIP-1alpha and RANTES. Furthermore, sera of HIV-infected hemophilia patients without AIDS or ARC had significantly higher anti-MIP-1alpha and anti-RANTES antibody activities than sera of HIV-infected hemophilia patients with AIDS. We speculate that the higher activities of anti-MIP-1alpha and anti-RANTES antibodies in asymptomatic HIV-1 infected individuals might be due to a cross-reaction of beta-chemokines with anti-V3-loop antibodies raised against gp120 of macrophage-tropic HIV-1 strains, known to be prevailing in the asymptomatic stage of HIV infection. Such anti-chemokine antibodies may play a deleterious role in the pathogenesis of AIDS by reducing the chemokines' potential to inhibit HIV-1 entry into CD4+ cells.