Key Points• AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells.• AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. We investigated the mechanisms by which AML causes pancytopenia and suppresses patients' immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic-severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34 1 progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through smallmolecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis. (Blood. 2013;122(5):749-758)

Invariant natural killer T (iNKT) cells are a unique population of T lymphocytes, which lie at the interface between the innate and adaptive immune systems, and are important mediators of immune responses and tumor surveillance. iNKT cells recognize lipid antigens in a CD1d-dependent manner; their subsequent activation results in a rapid and specific downstream response, which enhances both innate and adaptive immunity. The capacity of iNKT cells to modify the immune microenvironment influences the ability of the host to control tumor growth, making them an important population to be harnessed in the clinic for the development of anticancer therapeutics. Indeed, the identification of strong iNKT-cell agonists, such as a-galactosylceramide (a-GalCer) and its analogues, has led to the development of synthetic lipids that have shown potential in vaccination and treatment against cancers. In this Masters of Immunology article, we discuss these latest findings and summarize the major discoveries in iNKT-cell biology, which have enabled the design of potent strategies for immune-mediated tumor destruction.Cancer Immunol Res; 3(5); 425-35. Ó2015 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships. G. Dranoff-None. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflicts of interest to disclose. Learning ObjectivesResearch on the fundamental aspects of ab T-cell receptor (TCR) structure and function has informed infectious disease and oncology disciplines about the nature of cognate antigen recognition by the T-cell adaptive immune system. This information, in turn, will lead to effective development of CD8 T cell-based vaccines for preventive and immunotherapeutic purposes. Upon completion of this activity, the participant should gain a basic knowledge of the molecular structure of the ab TCR and the mechanobiology that allows a TCR to recognize a distinct foreign peptide among a myriad of antigens bound to the major histocompatibility complex with the required sensitivity and specificity for host protection.

The MHC is central to the adaptive immune response. The human MHC class II is encoded by three different isotypes, HLA-DR, -DQ, and -DP, each being highly polymorphic. In contrast to HLA-DR, the intracellular assembly and trafficking of HLA-DP molecules have not been studied extensively. However, different HLA-DP variants can be either protective or risk factors for infectious diseases (e.g. hepatitis B), immune dysfunction (e.g. berylliosis), and autoimmunity (e.g. myasthenia gravis). Here, we establish a system to analyze the chaperone requirements for HLA-DP and to compare the assembly and trafficking of HLA-DP, -DQ, and -DR directly. Unlike HLA-DR1, HLA-DQ5 and HLA-DP4 can form SDS-stable dimers supported by invariant chain (Ii) in the absence of HLA-DM. Uniquely, HLA-DP also forms dimers in the presence of HLA-DM alone. In model antigen-presenting cells, SDS-stable HLA-DP complexes are resistant to treatments that prevent formation of SDS-stable HLA-DR complexes. The unexpected properties of HLA-DP molecules may help explain why they bind to a more restricted range of peptides than other human MHC class II proteins and frequently present viral peptides.