A method for identifying clonotypes of antigen-specific T cells in a sample comprising T cells, the method comprising the steps of: (a) exposing the sample to a plurality of antigens in a plurality of different reaction mixtures, wherein each antigen of said plurality of antigens is present in a predetermined unique subplurality of the plurality of reaction mixtures; (b) selecting antigen-specific T cells from each of the plurality of reaction mixtures; (c) sequencing recombined nucleic acids encoding clonotypes of the same T cell receptor segment from: (i) the antigen-specific T cells selected in step (b) from each of the plurality of reaction mixtures, wherein the sequencing produces a plurality of sequence reads for each reaction mixture from which clonotypes and clonotype frequencies are determined, and (ii) T cells obtained from the sample prior to step (a), wherein the sequencing produces a plurality of sequence reads from which clonotypes and clonotype frequencies are determined; (d) for each reaction mixture, comparing the clonotype frequencies determined in step (c)(i) with the clonotype frequencies determined in step (c)(ii); and (e) for each of the plurality of antigens, identifying a clonotype of an antigen-specific T cell that has an increased frequency in each of the reaction mixtures in which the antigen was present and does not have an increased frequency in each of the reaction mixtures in which the antigen was absent. (a) exposing the sample to a plurality of antigens in a plurality of different reaction mixtures, wherein each antigen of said plurality of antigens is present in a predetermined unique subplurality of the plurality of reaction mixtures; (b) selecting antigen-specific T cells from each of the plurality of reaction mixtures; (c) sequencing recombined nucleic acids encoding clonotypes of the same T cell receptor segment from: (i) the antigen-specific T cells selected in step (b) from each of the plurality of reaction mixtures, wherein the sequencing produces a plurality of sequence reads for each reaction mixture from which clonotypes and clonotype frequencies are determined, and (ii) T cells obtained from the sample prior to step (a), wherein the sequencing produces a plurality of sequence reads from which clonotypes and clonotype frequencies are determined; (i) the antigen-specific T cells selected in step (b) from each of the plurality of reaction mixtures, wherein the sequencing produces a plurality of sequence reads for each reaction mixture from which clonotypes and clonotype frequencies are determined, and (ii) T cells obtained from the sample prior to step (a), wherein the sequencing produces a plurality of sequence reads from which clonotypes and clonotype frequencies are determined; (d) for each reaction mixture, comparing the clonotype frequencies determined in step (c)(i) with the clonotype frequencies determined in step (c)(ii); and (e) for each of the plurality of antigens, identifying a clonotype of an antigen-specific T cell that has an increased frequency in each of the reaction mixtures in which the antigen was present and does not have an increased frequency in each of the reaction mixtures in which the antigen was absent.