Th1- or Th2-cell commitment during infectious disease: an oversimplification?: Response from Jankovic, Liu and Gause

We appreciate the insights to our review1xTh1- and Th2-cell commitment during infectious disease: asymmetry in divergent pathways. Jankovic, D. et al. Trends Immunol. 2001; 22: 450–457Abstract | Full Text | Full Text PDF | PubMed | Scopus (177)See all References1 provided by Graham Rook and would like to respond to his comments. Sometimes even basic tenets of immunology that are described in undergraduate textbooks have to be revisited and refined in the light of new findings. Although we agree entirely that it is incorrect to attribute a more significant contribution to the host defense against pathogens to either the T helper 1 (Th1)- or Th2-type response, we do not believe that this precludes the possibility that Th1- and Th2-cells develop through pathways that are not parallel. Furthermore, preconceived, teleological speculations concerning the evolution of the immune system are frequently misleading.Clear differences are observed in the role of polarizing cytokines in directing the commitment of Th1- versus Th2-subsets during infectious disease. The generation of Th1 cells is dependent on soluble mediators secreted by antigen-presenting cells [primarily interleukin-12 (IL-12) but also, IL-18, interferon α/β (IFN-α/β) and IL-23], whereas sufficient IL-4 to initiate the differentiation of Th2 cells is produced by CD4+ T lymphocytes, independent of signaling through the IL-4R and/or STAT-6. This difference in the degree of developmental autonomy represents a crucial element of asymmetry between Th1- and Th2-pathways.It is difficult to ignore the fact that microbial stimuli known to interact with Toll-like receptors (TLRs) are also known to sensitize dendritic cells (DCs) for the priming of Th1 cells. To date, ≈50% of the members of the TLR family have been shown to be involved in the recognition of pathogens associated with Th1 responses, mainly bacteria and viruses2xToll meets bacterial CpG-DNA. Wagner, H. Immunity. 2001; 14: 499–502Abstract | Full Text | Full Text PDF | PubMed | Scopus (141)See all References, 3xDendritic-cell function in Toll-like receptor- and MyD88-knockout mice. Kaisho, T. and Akira, S. Trends Immunol. 2001; 22: 78–83Abstract | Full Text | Full Text PDF | PubMed | Scopus (271)See all References. It is probable that additional members of this family, and perhaps members of other gene families acting alone or in conjunction with TLRs, will be identified as receptors for microbial structures that induce the development of Th1 cells. Some of these receptors might also serve to discriminate between commensal and pathogenic bacteria. By contrast, pattern recognition receptors that trigger a Th2 response have not been identified yet. As we state throughout our review1xTh1- and Th2-cell commitment during infectious disease: asymmetry in divergent pathways. Jankovic, D. et al. Trends Immunol. 2001; 22: 450–457Abstract | Full Text | Full Text PDF | PubMed | Scopus (177)See all References1, it is possible, even probable, that pathogen-associated molecular patterns promoting the development of Th2 cells do exist. However, it is becoming increasingly apparent that Th2 cells can also develop in the absence of microbial adjuvants4xDendritic-cell regulation of Th1–Th2 development. Moser, M. and Murphy, K.M. Nat. Immunol. 2000; 1: 199–205Crossref | PubMedSee all References, 5xSee all References. These two alternative pathways to the development of Th2 cells are not mutually exclusive; one or the other might be used depending on the specific pathogen. Currently, the analysis of global gene expression in DCs exposed to different infectious agents is underway in several independent laboratories and thus, we can expect to learn much more about the molecular mechanisms that govern the priming of distinct subsets of Th cells in the near future.During infectious disease, the ongoing immune response depends on different regulatory mechanisms from those involved in initiation. Our review exclusively addresses the initial phase of the immune response to pathogens with respect to the development of Th1- and Th2-cells. At this early stage, certain pathogens are able to elicit immune responses with characteristics of both Th1- and Th2-responses, depending on the host environment (see Fig. 2 of Ref. 1xTh1- and Th2-cell commitment during infectious disease: asymmetry in divergent pathways. Jankovic, D. et al. Trends Immunol. 2001; 22: 450–457Abstract | Full Text | Full Text PDF | PubMed | Scopus (177)See all References1). Nevertheless, a clear distinction should be made between this phenomenon and the mixed, ‘aberrant’ cytokine-secretion responses in chronic infections associated with immunopathology, which might be due to other types of cell besides CD4+ lymphocytes. Finally, because they secrete cytokines that regulate the immune response, Th cells can also function as regulatory T cells, blurring this distinction.In addition to validating the Th1–Th2 concept, infectious disease models have provided an important basis for our understanding of the differentiation pathways of Th cells, and we believe that they will continue to play a major role in the in vivo analysis of these processes.