T h1/T h2 lymphocytes: Doubt some more

Abstract

The concept of T helper lymphocyte heterogeneity with T,~ and TH2 subclasses, which can be distinguished on the basis of their cytokine repertoire, has been a useful paradigm in studies on the immunology of allergic disorders? T m cells are generally defined by their synthesis of IL-2, interferon (IFN)--/, and tumor necrosis factor-J3 and are involved in cellular immunity; whereas T.2 cells are reported to produce IL-4, IL-5, IL-9, IL-10, and IL-13 and are involved in humoral immune responses and allergy. This paradigm has led to the concept that T helper lymphocyte responses to allergens are T.2-1ike in allergic subjects and Tin-like in nonallergic subjects, and as such, immunotherapy should work by converting T,2 into T.1 responses. Although appealing in its simplicity, the true nature of cytokine responses to antigens is much more complex than can be explained by this Tm/TH2 dichotomy. In most immune responses, T cells do not develop distinct Tm/T~2 cytokine profiles, but rather many different cytokine combinations. Restricted cytokine profiles are primarily observed after the generation of antigenspecific clones but are implied by in vivo and ex vivo pathology. However, cloning is an artifactual process, and the result does not necessarily reflect the physiologic response to the antigen. The repeated pulse stimulation with antigen, the physical chemical nature and dose of the antigen, the choice of antigen-presenting cell, the requirement for cytokine growth factors to maintain T-cell viability, and many other variables will all influence T helper differentiation. There are additional caveats concerning this differentiation in vitro of Tm/T~2 lymphocytes. No firm differentiation markers exist that distinguish a Tm from a T~2 cell, and these subgroups may not represent distinct subpopulations. The situation in human beings is additionally confused by significant limitations concerning the clear distinction between the cytokine profiles of TH1 and TH2 cells. In human beings, both subsets may make IL-2, IL-10, and IL-13 in addi-