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Can we apply the TH1-TH2 paradigm to all lymphocytes?

Nature Immunology volume 2, pages 899–900 (2001)Cite this article

The TH1-TH2 paradigm, in which CD4+ T cells polarize into type 1 or type 2 helper cells, has been extended to other cells types. However, evidence now suggests that NK cells differentiate sequentially from immature type 2 to mature type 1 cells, a pathway that could apply to other lymphocytes.

This new and provocative idea emerges from a long-standing goal of Perussia's group to characterize the development of human NK cells. NK cells contribute to early, nonadaptive, host responses to pathogens by perforin- and granzyme-mediated cytotoxicity and release of type 1 cytokines, such as IFN-γ. In earlier studies, Perussia and colleagues obtained human immature NK cells by culturing in vitro lineage-negative umbilical cord blood cells in the presence of IL-2 and stem cell factor9. These immature NK cells lack the classical NK cell marker CD56 and other activating or inhibitory NK cell receptors with the exception of NKR-P1 (CD161). Most importantly, they lack the IFN-γ transcript and lyse target cells through tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), rather than by releasing perforin and granzyme9,10. Later, a small population of NK cells with similar characteristics were identified in the blood; these cells produce type 2 cytokines, such as IL-13 and IL-5, and proliferate in the presence of IL-4 (M. J. Loza et al., unpublished data). In their latest study8, Loza and Perussia show that these type 2 NK cells are, indeed, immature NK cells. When cultured with IL-12, type 2 NK cells first differentiate into intermediate type 0 NK cells, which produce both IL-13 and IFN-γ, and then into mature type 1 NK cells, which produce IFN-γ and are capable of perforin-mediated cytotoxicity. This sequential differentiation is paralleled by de novo expression of CD56, CD8, the activating receptor NKp46 and the inhibitory major histocompatibility complex (MHC) class I–binding receptor CD94. IL-12–induced differentiation is irreversible, as type 1 NK cells do not revert to type 2 NK cells in the presence of IL-4. In fact, type 1 NK cells are terminally differentiated cells, which are competent for effector functions and subsequent programmed cell death (Fig. 1b).

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Figure 1: According to the TH1-TH2 paradigm (a), NK cell precursors (pre-NK) differentiate into NK cells producing either type 1 (NK1) or type 2 (NK2) cytokines, paralleling differentiation of TH precursors (pre-TH) into TH1 and TH2.

Bob Crimi

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  1. Basel Institute for Immunology, 487 Grenzacherstrasse, Basel, CH-4005, Switzerland

    Marco Colonna

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Colonna, M. Can we apply the TH1-TH2 paradigm to all lymphocytes?. Nat Immunol 2, 899–900 (2001). https://doi.org/10.1038/ni1001-899

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