Similarly, Th2 cells fit the description of a prime suspect during the development of atopy and subsequent allergic reactions, but their sole involvement and subsequent targeting for allergy therapy (which has only achieved modest success9) is unlikely.

Hence, neither the Th2 cell, at a particular snapshot in time of analysis, or its associated cytokine profile after unphysiological stimulation in vitro, should be thought of alone, but rather in the context in which it is acting. These rather obvious reminders are often not observable during in vitro Th2 experiments or are not reported buy ABT-263 during complex in vivo studies. Yet to accurately report a Th2-dependent gene, to hypothesize and test the function of Th2 features and to ascribe some relevant meaning requires an appropriate environment. Th2 cells and their responses are often vaguely described as type 2 microenvironments, expanding the single Th2 cell to a multi-cytokine and multi-cell mélange including alternatively activated macrophages, eosinophils, basophils, mast cells and recently described innate-like cells. We will attempt to strip down these broad interpretations and draw attention

to what we know and do not know about the type-2 namesake, αβ+ CD4+ Th2 cells. The activation of the il4 gene in CD4+ Th cells is the conventional marker for Th2 differentiation similar to the activation of the ifng gene for Th1 differentiation (Fig. 1). These markers have LDK378 supplier been used to identify the specific requirements

for Th2, or Th1, differentiation in vitro, in vivo, in situ and ex vivo. Most of our current understanding of Th2 differentiation is therefore based upon the activation of this single gene. What about cells that do not activate il4, either naturally or through genetic manipulation of the il4 gene or il4 receptor, but display other Th2 markers? Are they still Th2 cells? Indeed, IL-4-independent Th2 differentiation has been reported10–12 and will be discussed in more detail below. Reductionist Protein kinase N1 in vitro experiments have been invaluable, forging ahead and undressing Th2 (and other CD4+ Th) cell differentiation down to three essential signals, (i) TCR engagement, (ii) appropriate co-stimulation, and (iii) cytokine receptor ligation (Fig. 2). Needless to say, discrepancies exist between in vitro and in vivo requirements for each Th subset. T-cell receptor engagement, activating nuclear factor of activated T cell (NFAT) and GATA-binding protein-3 (GATA 3)13 may be the first signal to nudge CD4+ Th cells down a Th2 path. In seminal studies by Constant et al.12 and Hosken et al.