To determine the tissue-specific functions of SOCS-1, mice were generated in which the SOCS-1 gene could be deleted in individual tissues. A reporter gene of SOCS-1 promoter activity was also inserted. Using the reporter, high SOCS-1 expression was found at the CD4⁺CD8⁺ stage in thymocyte development. To investigate the function of this expression, the SOCS-1 gene was specifically deleted throughout the thymocyte/T/NKT cell compartment. Unlike SOCS-1^−/− mice, these mice did not develop lethal multiorgan inflammation but developed multiple lymphoid abnormalities, including enhanced differentiation of thymocytes toward CD8⁺ T cells and very high percentages of peripheral CD8⁺ T cells with a memory phenotype (CD44^hiCD25^loCD69^lo). These phenotypes were found to correlate with hypersensitivity to the γ-common family of cytokines.