Identification of T cells responding to a self-protein modified by an external agent.

An interesting class of immune responses is that in which an environmental agent modifies a self-protein. Heparin induced thrombocytopenia (HIT) is associated with an antibody response in which the immunogen is a self-protein, platelet factor 4 (PF4), modified by an external agent, heparin. We tested the hypothesis that a T cell component exists in HIT, which like the humoral response, also requires the combination of heparin and PF4 to be activated. We identify here, a subset of T cells derived from a subject with severe HIT, which were expanded preferentially in 14-day in vitro cultures specifically in the presence of PF4:heparin complexes. A combination of T cell receptor spectratyping, CDR3 sequencing, and clonotype-specific probe hybridization were used to identify the responding T cells. The three BV17 T cell "clonotypes" thus identified had a CDR3 length of 10 amino acids, used BJ1.2, and displayed a conserved CDR3 sequence motif. These T cells are an example of a cellular response to environmentally altered self and are likely to be directly involved in HIT by functioning as T helper cells. The results are discussed in terms of the possible role of modification of antigen presentation by the external agent in this response.