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Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory

Abstract

Emerging evidence indicates that CD8+ and CD4+ T-cell immunity is differentially regulated. Here we have delineated differences and commonalities among antiviral T-cell responses by enumeration and functional profiling of eight specific CD8+ and CD4+ T-cell populations during primary, memory and recall responses. A high degree of coordinate regulation among all specific T-cell populations stood out against an approximately 20-fold lower peak expansion and prolonged contraction phase of specific CD4+ T-cell populations. Surprisingly, although CD8+ T-cell memory was stably maintained for life, levels of specific CD4+ memory T cells gradually declined. However, this decay, which seemed to result from less efficient rescue from apoptosis, did not affect functionality of surviving virus-specific CD4+ T cells. Our results indicate that CD4+ T-cell memory might become limiting under physiological conditions and that conditions precipitating CD4+ T-cell loss might compromise protective immunity even in the presence of unimpaired CD8+ T-cell responses.

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Figure 1: Identification of virus-specific T cells.
Figure 2: Enumeration of epitope-specific CD4+ and CD8+ T cells from activation into lifetime memory.
Figure 3: Decay of specific CD4+ T-cell memory.
Figure 4: Coordinate regulation of antiviral T-cell responses irrespective of immunodominant determinants and T-cell lineage.
Figure 5: Functionality of specific CD4+ T cells and apoptosis regulation.
Figure 6: Coordinate regulation and complete mobilization of aged memory T cells during recall responses.

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Acknowledgements

We thank V. Apostolopolous and V. Mallet-Designé for help with MHC class II tetramer preparation and staining; A. Saluk and J. Trotter for assistance with 5- and 6-color flow cytometry; and M. von Herrath, M. Manchester, J. Sprent and I. Abramson for insightful discussions. This work is supported by NIH grants AG-04342 and AI-09484 (to M.B.A.O.) as well as NIH training grant AG-00080 and Juvenile Diabetes Foundation International fellowship 3-1999-629 (to D.H.).

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Correspondence to Dirk Homann.

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Homann, D., Teyton, L. & Oldstone, M. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat Med 7, 913–919 (2001). https://doi.org/10.1038/90950

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