DBA/1 mice immunized with native chick type II collagen (NcII) emulsified in complete Freund s adjuvant develop arthritis, whose underlying mechanisms are still undefined. As an initial step to studying the role of T cells in collagen-induced arthritis (CIA), we have established T cell lines specific to type II collagen. Characterizations of the antigen-induced proliferative responses mediated by these T cells have been reported. In essence, two major populations of collagen-reactive T cells were isolated: those that responded mainly to denatured type II collagen (DcII) and another group that reacted with both DcII and NcII. As shown in the present study, all of the collagen-reactive T cell lines isolated were found to be functional, although they differed in their capacity to mediate helper activities assessed by different assays. Hence, both populations of T cells exhibited the ability to trigger B cell proliferation, whereas only the population that recognized both DcII and NcII was capable of activating the synthesis of immunoglobulins by B cells. T cells from this latter group also provided specific help for the generation of a secondary anti-DNP antibody response. In addition, these T cells were capable of activating NcII-specific B cells to produce anti-collagen antibodies. By contrast, the T cell lines that reacted exclusively to DcII failed to mediate such specific helper functions. The inability of such T cells to activate DNP-primed B cells upon challenge with DNP-DcII did not appear to be due to a modification of antigenic sites on DcII by haptenation. Inasmuch as the DcII-specific T cell lines also proliferate less well in response to DcII than the T cell lines that recognize both DcII and NcII, a difference in the nature of the antigen receptors expressed by the two populations of collagen-specific T cells may partly explain the above observations. However, the inability to generate appropriate factors required for further differentiation of B cells to produce antibodies may also account for the failure of DcII-specific T cells to activate DNP-primed B cells. Finally, both populations of T cells were capable of mediating specific delayed-type hypersensitivity response.