EDITOR’S CAORNER OncoImmunology 1:3, 355-337; May/June 2012; © 2012 Landes Bioscience AUTHOR’S VIEW Invariant natural killer T cells reconstitution and the control of leukemia relapse in pediatric haploidentical hematopoietic stem cell transplantation Giulia Casorati,* Claudia de Lalla and Paolo Dellabona Experimental immunology Unit; Division of Immunology; Transplantation and Infectious Diseases; San Ra!aele Scienti"c Institute; Milano, Italy Keywords: NKT cells, CD1d, immunesurveillance, leukemia, immunotherapy CD1d-restricted invariant (i)NKT cells are innate-like, lipid-reactive T lymphocytes implicated in the control of infections, cancer and autoimmunity. Our study suggests that the reconstitution of the peripheral iNKT cell compartment, following HLA-haploidentical hematopoietic stem cell transplantation, associates with leukemia control in children a!ected by di!erent hematological malignancies. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes bearing con- served invariant V 14-J 18 V 24-J 18 TCR chains in mice and humans, respec- tively, paired with V 8, V 7 and V 2 in mice and V 11 in humans.1 iNKT cells recognize microbial and cell-endogenous lipids presented by the MHC class I-like molecule CD1d.1 iNKT cells acquire con- stitutive effector functions following lin- eage-dependent developmental cues, which enables them to rapidly respond to a variety of stimuli without prior Agsensitization. Upon activation, iNKT cells produce copi- ous amounts of different cytokines and they have been implicated in the early control of cell stress and tissue damage related to infec- tions, cancer and autoimmunity.1 The HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) is a criti- cal therapy for the great majority (75%) of leukemia patients lacking an HLA-identical sibling.2 The transfer of HSC from rela- tives that only share half HLA locus with the recipients permits to ﬁnd an immedi- ate donor for any patient.2 Puriﬁed donor- derived HSC are depleted of mature T cells to reduce the risk of GVHD, triggered by the donor/recipient histocompatibility barrier, and infused into patients who are profoundly myeloablated to eliminate both endogenous hemopoiesis and malignant cells.2 As a result, the immune system that reconstitutes in the recipients derives from the donor HSCs, which generate lymphoid precursors that seed in the thymus and give raise to the T and iNKT lymphocytes that are exported in the periphery.3 This process is particularly efﬁcient in pediatric patients who maintain a functional thymus.3 A rapid immunorecon- stitution is critical to control the major life threatening events that may occur following hHSCT, such as opportunistic infections and the leukemia recurrences.3 In light of these characteristics, we thought that hHSCT in pediatric patients with leukemia was a suit- able model to investigate human iNKT cell reconstitution, to address the unsolved issues of their maturation dynamics and their role in leukemia relapse control. Due to the dif- ﬁculty to follow longitudinally the iNKT cell development in healthy donors, only snap- shots on the human iNKT cell development at initial (thymus and umbilical cord blood) or late (adult blood) stages were available from cross-sectional studies, showing that: (1) Thymic and neonatal iNKT cells display an immature CD4+ phenotype lacking CD161, the NK terminal differentiation marker, and poor effector cytokine production;4 (2) adult mature circulating iNKT cells are divided into two main CD4+CD161+ T 0 helper/regula- H tory and CD4- CD161+ (mainly CD4-CD8-) TH1 effector/inﬂammatory subsets with a CD4- CD4+ ratio.5,6 However, the dynam- ics by which an immature fetal CD4+161- precursor generates the two adult mature CD4+CD161+ and CD4-CD161+ iNKT cell subsets was unknown. On the other hand, evidence in mouse models and cancer patients suggested that iNKT cells participate in the immune surveillance of different solid tumors, lymphoma and multiple myeloma.7 Pre-clinical studies also elucidated the iNKT cell role in determining the positive balance between GVL and GVHD in mouse models of HSCT for leukemia.8 Hence, the potential control of leukemia relapses by human iNKT in the clinically relevant context of hHSCT was an important question. In our study,9 we undertook a thor- ough longitudinal analysis of iNKT cell reconstitution in 22 consecutive pediat- ric patients undergoing hHSCT after a myeloablative regimen for the treatment of acute leukemia and myelodysplastic syn- dromes (Fig. 1A). CD4+ and CD4- iNKT cell frequency, number, phenotype and effector functions were assessed, in direct comparison with mainstream T cells, in *Correspondence to: Giulia Casorati; Email: casorati.giulia@hsr.it Submitted: 10/07/11; Revised: 10/11/11; Accepted: 10/13/11 http://dx.doi.org/10.4161/onci.18399 www.landesbioscience.com OncoImmunology 355