Distinct autoreactive T cell responses to native and fragmented DNA topoisomerase I: influence of APC type and IL-2.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which T cell responses to various autoantigens, including DNA topoisomerase I (Topo I), have been implicated. We investigated whether dendritic cells, generally considered to be the most potent APCs for the initiation of immune responses, would present either of two forms of Topo I to T cells more efficiently than PBMC APCS: Using cells from healthy controls and SSc patients, several important observations were made. First, neither APC type was able to initiate T cell proliferative responses to full-length native Topo I unless exogenous IL-2 was added. This is in contrast to vigorous T cell proliferation in response to Topo I polypeptide fragments presented by either APC type. Second, T cell responses to the full-length form of Topo I presented by dendritic cells were considerably lower than responses to Ag presented by PBMC APCS: Finally, no secondary T cell responses were observed unless the same Ag/APC combination as that used in the primary stimulation was maintained. These data indicate that different peptides are generated based upon the form of the Topo I and the APC that processes it. Taken together, these results suggest that a very specific combination of antigenic form and APC may be involved in breaking tolerance to Topo I in the early stages of development of SSC: