Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity

Abstract

The main functions of memory T cells are to provide protection upon re-exposure to a pathogen and to prevent the re-emergence of low-grade persistent pathogens. Memory T cells achieve these functions through their high frequency and elevated activation state, which lead to rapid responses upon antigenic challenge. The significance and characteristics of memory CD8+ T cells in viral infections have been studied extensively. In many of these studies of T-cell memory, experimental viral immunologists go to great lengths to assure that their animal colonies are free of endogenous pathogens in order to design reproducible experiments. These experimental results are then thought to provide the basis for our understanding of human immune responses to viruses. Although these findings can be enlightening, humans are not immunologically naïve, and they often have memory T-cell populations that can cross-react with and respond to a new infectious agent or cross-react with allo-antigens and influence the success of tissue transplantation. These cross-reactive T cells can become activated and modulate the immune response and outcome of subsequent heterologous infections, a phenomenon we have termed heterologous immunity. These large memory populations are also accommodated into a finite immune system, requiring that the host makes room for each new population of memory cell. It appears that memory cells are part of a continually evolving interactive network, where with each new infection there is an alteration in the frequencies, distributions, and activities of memory cells generated in response to previous infections and allo-antigens.

Figure 1

(A ) Hierarchy of lymphocytic choriomeningitis virus (LCMV) epitope‐specific memory populations which expand upon vaccinia virus (VV) infection. Determined by private specificity of the T‐cell receptor (TCR) repertoire of each individual mouse, NP₂₀₅(50% of mice) > GP₃₄(23%) > GP₁₁₈(15%). (B) Structural modeling demonstrates similar structures evident in areas important for TCR interaction between VV a11r₁₉₈ and LCMV GP₁₁₈, LCMV GP₃₄, LCMV NP₂₀₅, and VV e7r₁₃₀. Using the concept of molecular mimicry, LCMV epitopes were identified that induced cross‐reactive CD8⁺ T‐cell responses recognizing the VV a11r₁₉₈ epitope (shown in green). The arrows mark positions 4, 7 (white), and 6 (yellow), which are important for TCR interaction. For modeling 3‐D structures of putative peptide‐H‐2K^b complexes, we used X‐ray coordinates of the crystallized TCR(2C)–dEV8–H‐2K^b (PDB access number 2CKB). Using Swiss‐PDB Viewer software (GlaxoSmithKline R & D, Geneva, Switzerland), we mutated dEV8 to simulate the peptides whose sequences are shown in (B). The modified variants with minimal rotamer penalties were subjected to an energy minimization protocol. For graphical presentation of the simulated peptide‐H‐2K^b complexes, PyMol software (DeLano scientific LLC, San Carlos, California) was utilized. The H‐2K^b‐restricted ovalbumin epitope, SIINFEKL, is shown as the actual crystal structure adapted from PDB access number 1VAC (185).

Figure 2

Cross‐reactive CD8⁺ T‐cell matrix. The Epstein – Barr virus BMLF1₂₈₀ peptides induce CD8⁺ T‐cell responses that cross‐react with four other CD8⁺ T‐cell populations. The influenza M1₅₈ peptide can induce CD8⁺ T‐cell responses that cross‐react with at least three other CD8⁺ T‐cell populations. Which cross‐reactive pattern any individual displays depends on the private specificity of each individual's T‐cell receptor repertoire. The numbers in the figure indicate how many individuals of the total tested demonstrated the predominant cross‐ reactive response indicated (the thickness of arrows correlates with the frequency).

Figure 3

Dynamics of the CD8⁺ T‐cell response during sequential heterologous virus infections. This figure demonstrates the kinetics of virus growth, interferon synthesis, virus‐induced lymphopenia, T‐cell expansion and then apoptotic decline, and stability of CD8⁺ memory in mice infected with lymphocytic choriomeningitis virus. It shows the enhancement of T cells specific to cross‐reactive (cxr) and the attrition against non‐cxr epitopes after challenge with a heterologous virus, such as Pichinde virus. Reprinted, with permission, from the Annual Reviews of Immunology, Volume 22 ©2004 by Annual Reviews http://www.annualreviews.org.