Although the immune system has long been implicated in the control of cancer, evidence for specific and efficacious immune responses in human cancer has been lacking. In the case of chronic myelogenous leukemia (CML), either allogeneic bone marrow transplant (BMT) or interferon-alpha2b (IFN-alpha2b) therapy can result in complete remission, but the mechanism for prolonged disease control is unknown and may involve immune anti-leukemic responses. We previously demonstrated that PR1, a peptide derived from proteinase 3, is a potential target for CML-specific T cells. Here we studied 38 CML patients treated with allogeneic BMT, IFN- alpha2b or chemotherapy to look for PR1-specific T cells using PR1/HLA-A*0201 tetrameric complexes. There was a strong correlation between the presence of PR1-specific T cells and clinical responses after IFN-alpha and allogeneic BMT. This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells.

Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1–restricted Mtb lipid–specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, group 1 CD1–restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that group 1 CD1–restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines.

Group 1 CD1 (CD1a, -b, and -c) presents self and foreign lipid antigens to multiple T-cell subsets in humans. However, in the absence of a suitable animal model, the specific functions and developmental requirements of these T cells remain unknown. To study group 1 CD1-restricted T cells in vivo, we generated double transgenic mice (HJ1Tg/hCD1Tg) that express group 1 CD1 molecules in a similar pattern to that observed in humans (hCD1Tg) as well as a TCR derived from a CD1b-autoreactive T-cell line (HJ1Tg). Using this model, we found that similar to CD1d-restricted NKT cells, HJ1 T cells exhibit an activated phenotype (CD44 hi CD69 ؉ CD122 ؉ ) and a subset of HJ1 T cells expresses NK1.1 and is selected by CD1b-expressing hematopoietic cells. HJ1 T cells secrete proinflammatory cytokines in response to stimulation with CD1b-expressing dendritic cells derived from humans as well as hCD1Tg mice, suggesting that they recognize species conserved self-lipid antigen(s). Importantly, this basal autoreactivity is enhanced by TLR-mediated signaling and HJ1 T cells can be activated and confer protection against Listeria infection. Taken IntroductionThe CD1 antigen-presenting molecules are similar in structure to MHC class I, but are specialized to present lipid antigens to T cells. 1 These antigens include mammalian self-lipids and foreign lipids derived from specific microorganisms that are loaded onto CD1 in the endosomal compartments of the cell. [2][3][4][5][6] Five members of the CD1 family have been identified and can be classified into 3 groups based on sequence homology. 7 Group 1 CD1 (CD1a, b, and c) and group 2 CD1 (CD1d) are expressed on the cell surface and act as antigen-presenting molecules, while CD1e acts as a chaperone to facilitate lipid delivery onto CD1b and CD1d molecules. 8 While humans express all CD1 isoforms, muroid rodents only express CD1d. 1 To date, CD1d has been the most extensively studied member of the CD1 family. CD1d presents lipid antigens to a unique subset of T cells, NKT cells. The best-known subset of CD1d-restricted NKT cells uses an invariant TCR␣ chain (V␣14-J␣18 in mice and V␣24-J␣18 in humans); they are therefore referred to as invariant NKT (iNKT) cells. 9 Unlike most conventional T cells, iNKT cells exhibit an activated phenotype which is partly the results of their positive selection being mediated by CD1d-expressing thymocytes, instead of thymic epithelial cells. 10 iNKT cells rapidly secrete IFN-␥, IL-4, and other cytokines on TCR stimulation. 9,11,12 Activated iNKT cells in turn activate DC, macrophages and NK cells and thereby impact subsequent B and T-cell responses. 13 Therefore, iNKT cells play a critical role in bridging innate and adaptive immune responses.In contrast to iNKT cells, our knowledge regarding group 1 CD1-restricted T cells is largely limited to the observation of long-term cultured T-cell clones, as a suitable animal model has only recently been developed. 14 Group 1 CD1-restricted T-cell lines have been isolated from human patients infected with Mycobac...

IntroductionCD1d-restricted natural killer T (NKT) cells represent a unique lineage of T cells that shares properties with both natural killer (NK) cells and memory T cells. NKT cells rapidly produce an array of cytokines on activation and play critical roles in the regulation of a variety of immune responses, including control of autoimmune diabetes, antitumor immunity, and protection from infectious diseases. 1 To date, 2 NKT-cell subsets have been defined. Type I NKT cells, also referred to as invariant NKT (iNKT) cells, express an invariant T-cell receptor ␣ (TCR␣) chain (V␣14J␣18 in mice and V␣24-J␣18 in humans) that pairs with a limited repertoire of TCR␤ chains (V␤8, V␤7, or V␤2 in mice, and V␤11 in humans). 2 iNKT cells can be identified using CD1d tetramer loaded with the glycosphingolipid antigen ␣-galactosylceramide (␣GalCer). 3 Type II NKT cells represent the second subset of NKT cells; they exhibit diverse TCR␣ and TCR␤ chain usage and do not bind to CD1d/␣GalCer tetramers. 4 This study focuses on iNKT cells, because the various stages of iNKT-cell maturation and differentiation have been clearly defined.Like conventional T cells, iNKT cells originate from thymic CD4 ϩ CD8 ϩ double-positive (DP) progenitors. 5 However, the iNKTcell lineage deviates from conventional T cells at the DP stage, and their positive selection is distinct from that of conventional T cells. 6,7 Rare DP-precursor cells that express a rearranged V␣14J␣18 TCR␣ chain are positively selected by CD1d-expressing DP thymocytes that provide unique costimulatory signals to iNKT-cell precursors through homotypic interactions with signaling lymphocytic activation molecules (SLAM) family receptors. These interactions led to the recruitment of SLAMassociated protein (SAP) and the Src kinase Fyn, as well as downstream activation of nuclear factor-B (NF-B). [8][9][10][11][12] After positive selection, iNKT-cell precursors down-regulate their expression of CD24 and transition through several maturation stages that can be defined based on the cell-surface expression of CD44 and NK1.1. 13 Stage I iNKT cells display an NK1.1 Ϫ CD44 low phenotype and undergo several rounds of cell division. This expansion is accompanied by the up-regulation of CD44 (NK1.1 Ϫ CD44 high , stage II iNKT cells). Some of these NK1.1 Ϫ CD44 high iNKT cells continue to differentiate into mature NK1.1 ϩ CD44 high (stage III) iNKT cells in the thymus, while others exit the thymus and mature into NK1.1 ϩ iNKT cells in the periphery. 1,13,14 iNKT cells can also be subdivided into CD4 ϩ and CD4 Ϫ CD8 Ϫ (double-negative [DN]) subsets. The earliest iNKT cells are CD4 ϩ , with the DN subset diverging at the immature NK1.1 Ϫ stage in the thymus. 13,14 Recent studies have shown that the transcription factor Th-Pok is required for the repression of CD8 expression and the functional maturation of iNKT cells. 15,16 The unique developmental program of iNKT cells is controlled by several transcription factors/molecules that are distinct from those required for the development of conve...