A Critical Role of Costimulation during Intrathymic Development of Invariant NK T Cells

Abstract

CD1d-restricted Vα14+ invariant NK T (iNKT) cells are a specialized αβ T cell subset that regulates both innate and adaptive immunity. Although costimulatory molecules are required for the activation of conventional T cells and for the development of Foxp3+ T cells, their role in iNKT cell regulation is unclear. Here we report that mice deficient in CD80/CD86 and/or B7h exhibit severe defects in thymic iNKT cell maturation, associated with largely reduced iNKT cell number in the thymus and the periphery. We show that costimulation is necessary for the optimal expansion of postselected NK1.1− immature iNKT cells in the thymus and for the proper expression of the maturation markers T-bet and CD122. Surprisingly, costimulatory molecules on both hemopoietic and nonhematopoietic cells are required for iNKT cell development. Our results thus demonstrate a previously unknown function of costimulation in the intrathymic development of iNKT cells, distinct from that of conventional T cells and regulatory T cells.

Intrathymic proliferation wave essential for Vα14 + natural killer T cell development depends on c-Myc

“…In contrast to developing conventional T cells, intrathymic iNKT cell differentiation depends on agonist selection as well as costimulation (29). iNKT cells are not killed by negative selection on encounter of agonist but rather the receptor signal they receive places them in a ''standby'' mode, priming them for immediate response to further receptor challenge (1,7).…”

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

“…Fyn, SAP), transcription factors (e.g. NFκB, T-bet, Ets1, Runx1, RORγ, Itk, Rlk, AP-1) (see Ref [4] for reviews), and co-stimulatory molecules such as CD28 and ICOS [11]. Most iNKT cells leave the thymus in an immature stage (as defined by the absence of expression of NK receptors such as NK1.1) and fulfill their terminal maturation in the periphery [12][13][14].…”

Inflammation, Aging and Cancer: Friend or Foe?

“…Aging process is also associated with minor or major changes in immune response profiles and co-expression and co-existence of mismatched or misdirected inflammatory mediators (e.g., TNF-, IL-6, IFN-,, IFNs, PGE2, etc) features that are characteristics of immunoscenescence involved in a wide range of chronic diseases (Davalos et al 2010, Ginaldi et al, 2005, Chung et al, 2008, Khatami 2008, 2011a, Nagai et al, 2010, Ren et al, 2009, Romanyukha and Yashin 2003, Sansoni et al, 2008, Sedivy et al, 2008, Serbina et al, 2008, Siffrin et al, 2007, Zhang 2010 (Figures 3 and 4). Briefly, low grade (unresolved or subclinical) inflammation and longevity are known as comorbidity and co-mortality risk factors in the genesis and progression of nearly all chronic illnesses.…”

“…However, longevity and the rate of functional capacities of organ systems and susceptibility to chronic diseases vary in individuals, due to a combination of genetics, immunological or biological factors and the frequency of exposure to diverse environmental hazards. In an attempt to find a common forum on enormous amount of fragmentary information on the biology of chronic diseases that are linked to inflammation, highlights of major molecular theories of aging are outlined in the following (reviewed in Khatami 2009 (Deng et al, 2008, Ginaldi et al, 2005, Goronzy and Wevand 2005, Khatami 2009a, Nagai et al, 2010, Siffrin et al, 2007, Vasto et al, 2008, Zhang 2010 (Campisi 2011, Chidgev et al, 2007, Chung et al, 2008, Davalos et al, 2010, Deng et al, 2008, Gounaris et al, 2006, Khatami 2008a, Klein et al, 2009, Montavani et al, 2004, O'Brien et al, 2008, Romanyukha and Yashin 2003 (Figures 3 and 4). c. Hormones, Metabolites and Lipids in Biology of Aging: Aging process is associated with altered functions of important hormones (e.g., estrogen, progesterone, insulin, glucagon, androgen, andosterone, testosterone, thyroxine, glucocorticoids, epinephrine, cortisol, mineralcorticoids, dehydroepiandosterone-DHEA, etc) and hormone-like growth factors (e. g., IGF-1, FGF, EGF, VEGF, etc).…”