Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly. Characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis, pathophysiological causes of this disease are diverse including genetic abnormalities within myeloid progenitors, altered epigenetics, and changes in the bone marrow microenvironment. The concept that T-cell mediated autoimmunity contributes to bone marrow failure has been widely accepted due to hematologic improvement after immunosuppressive therapy (IST) in a subset of patients. Currently, IST for MDS primarily involves anti-thymocyte globulin (ATG)-based regimens in which responsiveness is strongly associated with younger (under 60 years) age at disease onset. In such cases, progressive cytopenia may occur as a consequence of expanded self-reactive CD8+ cytotoxic T lymphocytes (CTLs) that suppress hematopoietic progenitors. Although most hematologists agree that IST can offer durable hematologic remission in younger patients with MDS, an international clinical study and a better understanding of the molecular mechanisms contributing to the expansion of self-reactive CTLs is crucial. In this review, data accumulated in the US, Europe, and Asia will be summarized to provide insight and direction for a multi-center international trial.