Invariant NKT Cells as Initiators, Licensors, and Facilitators of the Adaptive Immune Response

In the past, the neural reflex arc provided immunologists with a useful analogy for understanding the adaptive immune response (Fig. 1). A revisit to the concept of the immune reflex arc, in which the immune response is divided into an afferent limb, central processing mechanism, and efferent limb, may help us understand where and how various innate immune cells function. Originally, the cells that were thought to be involved in the afferent limb were macrophages (M ␸) and DCs that had taken up and perhaps processed antigen before transporting the antigen to the secondary lymphoid organ. The central processing mechanism involves the interaction of T and B cells and the antigen-presenting cells (DCs) to generate effector cells and molecules. The efferent limb of the immune reflex arc begins once the ef-fector cells and molecules leave the lymphoid tissue and enter the efferent lymphatics and blood to find the tissue and the site of the antigen. Innate cells are involved in all three limbs of the immune reflex arc. During the afferent limb NK cells establish the cytokine milieu that biases the adaptive response toward a T helper type 1 (Th1) response. M ␾ and DCs transport the antigen to the lymphoid organ during the afferent limb. The ability of NK cells to lyse tumor cells and bacteria without a prior exposure contributes to the afferent limb by reducing the infectious antigen and allowing for a more effective outcome during the immune reflex arc. NK cells, M ␾ , and DCs have a major influence on the central processing mechanism since they are providing the cytokine microenvironment during antigen presentation. Once the effector cells leave the lymphoid organ, the innate cells may again participate during the efferent limb. For example, M ␾ and NK cells armed with antibody frequently mediate antibody-dependent cellular cytoxicity. Invariant NKT Cells. Although a minor population of T cells that expressed some NK cell markers was described in the late 1980s, the furor over the function of these cells didn't begin until the middle of the next decade (1, 2). It was shown that whereas the NKT cell exhibited some pheno-typic heterogeneity, ‫ف‬ 85% of the mouse NKT cell expressed an invariant TCR (V ␣ 14j ␣ 18) that was specific for the class I–like molecule, CD1d (referred to hereafter as iNKT cells). Early investigations suggested that the NKT cell might function early in immune responses to …