No one is naive: the significance of heterologous T-cell immunity

Key Points

  • CD8+ T-cell memory to viruses is stable, but memory is lost after infections with other viruses.

  • The homeostasis of CD8+ T-cell memory differs from that of CD4+ T-cell memory.

  • Crossreactive T-cell responses between heterologous viruses might be a common event.

  • The immunodominance of epitopes that are recognized by T cells is, in part, a function of a T-cell repertoire that is moulded by the past history of infection.

  • Viruses might cause the activation of memory T cells that are specific for previously encountered pathogens.

  • Memory T cells that are specific for unrelated pathogens might have roles in protective immunity and immunopathology caused by heterologous infectious agents.

  • Immune deviation, or the balance between T helper 1 (TH1) and TH2 responses, might be influenced by the memory T-cell pool that is specific for previously encountered pathogens.


Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a host's history of previous infections, and with each successive infection, T-cell memory to previously encountered agents is modified. Here, we discuss evidence from studies in mice and humans that shows the importance of this phenomenon in determining the outcome of infection.

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Figure 1: Potential mechanisms of T-cell crossreactivity.
Figure 2: Modulation of the T-cell repertoire during viral infection.
Figure 3: Protective heterologous immunity between viruses.
Figure 4: Model of heterologous immunity in the lung.
Figure 5: Comparison of pathology in fat and lung in models of heterologous immunity in mice, and in human diseases of unknown aetiology.


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R.M.W. and L.K.S. are supported by the United States National Institutes of Health. The contents of this article are solely the responsibility of the authors and do not represent the official views of the NIH. We thank M. Brehm, A. Fraire, I. Joris, B. Smoller and H. Chen for their collaborations and helpful comments.

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Correspondence to Liisa K. Selin.

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(TH1/TH2). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce IFN-γ, lymphotoxin and TNF, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoral immunity, and downregulate TH1 responses.


Optimal signalling through the TCR complex requires accessory cell-surface molecules, such as CD28 or LFA1. Signals that are delivered from these molecules contribute to enhancing the immune response. In the absence of these co-stimulatory signals, naive T cells become unresponsive to a subsequent challenge with antigen.


(5,6-carboxy-fluorescein diacetate succinimidyl ester). This a fluorescent dye that is used to label cells. With each cell division, the label is distributed equally into daughter cells. The loss of fluorescence intensity is used to calculate the number of cell divisions.


The term, as it is used here, refers to the activation of T cells in which the TCRs are not being triggered by the antigens that are driving the immune response. This activation might be mediated by cytokines.


Previous exposure to one virus strain diverts the antibody response after exposure to a second virus strain to epitopes that are shared between the two strains.


(BrdU). A thymidine analogue that can be incorporated into DNA during S-phase when cells are exposed to this substance. Cells that have incorporated BrdU, and presumably have divided, can be visualized with anti-BrdU antibodies using flow cytometry.

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Welsh, R., Selin, L. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol 2, 417–426 (2002).

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