We examined the antigen recognition of the class II major histocompatibility complex (MHC) of 45 poly(glu 6° ala 3° tyr ~ o) (GAT)=reactive T-cell clones isolated by limiting dilution cloning of a pool of in vivo-primed and in vitrorestimulated A.TL lymph-node T cells. Each clone expressed the Thy-1.2 +, Lyt-1 +, Lyt-2-, LFA-1 +, Ia-, and H-2D a+ cell-surface phenotype and exhibited strict specificity for GAT on syngeneic antigen-presenting cells (APCs). The monitoring of the proliferative responses of these clones in the presence or absence of GAT, using APCs from strains with 11 independent H-2 haplotypes, revealed several distinct specificity patterns: (i) most (31 of 45, 73%) T-cell clones recognized GAT in a self-I-Ak-restricted manner; (ii) other alloreactive clones (5 of 45, 11%) were stimulated to proliferate, irrespective of the presence of GAT, in response to allodeterminants expressed on H-2s, H-2 d, H-2 y or H-.2 u spleen cells; (iii) a third T-cell clone subset (4 of 45, 9%) was activated by GAT in the context of not only self-I-A k but also nonself restriction Ia determinants; and (iv) three clones (7%) exhibited a triple specificity, i. e., they recognized GAT in the context of self and nonself Ia determinants and were alloreactive. One of tl~e latter clones responded to GAT in an apparently non-MHC-restricted manner and recognized an I-A b allodeterminant. These data provide direct evidence that the antigen-specific and alloreactive T-cell repertoires overlap and that the self-MHC restriction of GAT-specific T-cell responses is not absolute in A.TL mice.