T follicular helper cells (Tfh cells) are a new subset of effector cells characterized by their presence in germinal centers, the production of IL-21 and their essential role as helper of B cells and antibody (IgG) production. However, unlike other T helper subsets, a certain degree of plasticity seems to be present in Tfh cells since they are not fully committed and can lose their phenotype, and different effector cells can become Tfh cells if the right environment is present. The factor/s contributing to this plasticity remain unknown. We have shown that IL-6, a cytokine derived by a number of innate immune cells and non-hematopoietic cells, is a unique factor necessary and sufficient to induce IL-21 production in naove and memory CD4 T cells. Our preliminary studies indicate the IL-6 is also able to enhance IL-21 production during the activation of effector Th1, Th2 and Th17 cells. We have also shown that IL-6 enhances antibody responses by indirectly acting on CD4 T cells, inducing their IL-21 production, and this IL-21 acting on B cells. We propose that IL-6 is a major innate immune factor that contributes to the plasticity of Tfh cells and thereby Ab production by tonically regulating IL-21 expression in CD4 T cells without a full commitment. We also propose that the plasticity caused by IL-6 is mediated by its effect on two independent signaling pathways, 1) STAT3, modulating mitochondrial metabolism, and 2) C/EBP2, providing selective expression of IL-21. IL-6-mediated plasticity may be key in the integration of the innate immune response with CD4 and B cell responses. We will determine 1) the contribution of IL-6 to the plasticity of Tfh cells by tonically inducing IL-21 production in naive, effector and memory CD4 T cells (Aim 1), 2) the contribution of STAT3 and C/EBP2 transcription factors to the IL-6 mediated plasticity of CD4 Tfh cells (Aim 2), 3) the role of IL-6 in protective antiviral memory response by promoting memory CD4 T cells to become Tfh cells (Aim 3).
The presence of neutralizing antibodies (Ab) against viruses (e.g. influenza virus) is one of the major protective mechanisms preventing secondary infections. Although primary infections and/or vaccines induce significant titers of Ab, the degree of protection against secondary infection is highly variable among individuals, and often insufficient. Understanding the factors that influence the Ab response during primary and secondary viral infection is highly significant because it may lead to the development of new strategies for vaccines as well as for treatments. While B cells produce Abs, they are highly dependent of the help of a specific CD4 T cell subset designed as Tfh cells (T follicular cells). We are interested in determining factors that can affect the quality and quantity of the help Tfh cells provide to B cells, how these factors influence the help capacity of Tfh cells, and their contribution to protection against influenza virus infection. Specifically, we will address the role of IL-6 on the generation and function of Tfh cells, and how this pro-inflammatory affects Ab production by B cells indirectly through Tfh cells. We propose that the presence of IL-6 is essential both during the primary infection as well as during a secondary infection for Tfh cells to provide help to B cells through IL-21. Our recent studies have shown that administration of IL-6 in combination with an influenza virus vaccine significantly increases the Ab response and the protection capacity of the vaccine. We now propose to examine the mechanism for this effect and also the role that IL-6 has on memory Tfh cells and Ab production in secondary infections. IL-6 levels are frequently modulated by different pathological conditions. Thus, our model would imply that, independently of the response to primary infection or vaccines, protection against secondary infection could be determined by the physiological or pathological conditions when the secondary infection occurs. In addition, there is a well-established polymorphism (genetic signature) in the regulatory region of the IL-6 gene widely distributed in the human population. Both of these factors could explain the heterogeneity in the response to influenza virus among individuals.
| Yang, Rui; Masters, April R; Fortner, Karen A et al. (2016) IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21-producing B helper CD8+ T cells. J Exp Med 213:2281-2291 |
| Yang, Rui; Rincon, Mercedes (2016) Mitochondrial Stat3, the Need for Design Thinking. Int J Biol Sci 12:532-44 |
| Yang, Rui; Lirussi, Dario; Thornton, Tina M et al. (2015) Mitochondrial Ca²? and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function. Elife 4: |
| Rincon, Mercedes; Irvin, Charles G (2012) Role of IL-6 in asthma and other inflammatory pulmonary diseases. Int J Biol Sci 8:1281-90 |
