Basic Principles in Modeling Adaptive Regulation and Immunodominance
In this chapter we overview our recent work on mathematical models for the regulation of the primary immune response to viral infections and immunodominance. The primary immune response to a viral infection can be very rapid, yet transient. Prior to such a response, potentially reactive T cells wait in lymph nodes until stimulated. Upon stimulation, these cells proliferate for a limited duration and then undergo apoptosis or enter dormancy as memory cells. The mechanisms that trigger the contraction of the T cell population are not well understood. Immunodominance refers to the phenomenon in which simultaneous T cell responses against multiple target epitopes organize themselves into distinct and reproducible hierarchies. In many cases, eliminating the response to the most dominant epitope allows responses to subdominant epitopes to expand more fully. Likewise, if the two most dominant epitopes are removed, then the third most dominant response may expand. The mechanisms that drive immunodominance are also not well understood.
KeywordsCell Response Effector Cell Cell Clone Phase Portrait Extended Model
This work was supported in part by the joint NSF/NIGMS program under Grant Number DMS-0758374 and in part by Grant Number R01CA130 817 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
- 6.Chang, C.C., Ciubotariu, R., Manavalan, J.S., Yuan, J., Colovai, A.I., Piazza, F., Lederman, S., Colonna, M., Cortesini, R., Dalla-Favera, R., Suciu-Foca, N.: Tolerization of dendritic cells by T(S) cells: The crucial role of inhibitory receptors ILT3 and ILT4. Nat. Immunol. 3(3), 237–243 (2002)CrossRefGoogle Scholar
- 9.De Boer, R.J., Homann, D., Perelson, A.S.: Different dynamics of CD4+ and CD8+ T cell responses during and after acute lymphocytic choriomeningitis virus infection. J. Immunol. 171(8), 3928–3935 (2003)Google Scholar
- 13.Kaech, S.M., Ahmed, R.: Memory CD8+ T cell differentiation: Initial antigen encounter triggers a developmental program in naïve cells. Nat. Immunol. 2(5), 415–422 (2001)Google Scholar
- 18.León, K., Lage, A., Carneiro, J.: How regulatory CD25+CD4+ T cells impinge on tumor immunobiology? On the existence of two alternative dynamical classes of tumors. J. Theor. Biol. 247(1), 122–137 (2007)Google Scholar
- 19.León, K., Lage, A., Carneiro, J.: How regulatory CD25+CD4+ T cells impinge on tumor immunobiology: The differential response of tumors to therapies. J. Immunol. 179(9), 5659–5668 (2007)Google Scholar
- 20.Mercado, R., Vijh, S., Allen, S.E., Kerksiek, K., Pilip, I.M., Pamer, E.G.: Early programming of T cell populations responding to bacterial infection. J. Immunol. 165(12), 6833–6839 (2000)Google Scholar
- 22.Probst, H.C., Dumrese, T., van den Broek, M.F.: Cutting edge: Competition for APC by CTLs of different specificities is not functionally important during induction of antiviral responses. J. Immunol. 168(11), 5387–5391 (2002)Google Scholar
- 28.Trimble, L.A., Lieberman, J.: Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signalling chain of the T-cell receptor complex. Blood 91(2), 585–594 (1998)Google Scholar
- 29.van der Most, R.G., Murali-Krishna, K., Lanier, J.G., Wherry, E.J., Puglielli, M.T., Blattman, J.N., Sette, A., Ahmed, R.: Changing immunodominance patterns in antiviral CD8 T-cell responses after loss of epitope presentation or chronic antigenic stimulation. Virology 315(1), 93–102 (2003)CrossRefGoogle Scholar
- 31.van Stipdonk, M.J., Lemmens, E.E., Schoenberger, S.P.: Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2(5), 423–429 (2001)Google Scholar