Immunological memory within the innate immune system

Abstract

Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen-specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings.

Keywords: NK cells; immunity; innate immunity; memory.

Figure 1. Mechanisms for antigen specificity and memory in vertebrates and invertebrates

In higher vertebrates (from jawed fish to mammals), antigen specificity and immune memory are mediated by lymphocytes possessing rearranged antigen receptors. In lower vertebrates such as lampreys and hagfish (jawless fish), VLRs containing leucine-rich repeats could be responsible for a primitive form of adaptive immunity. In invertebrates (from shellfish to worms and insects), the diversity of antigen receptors is likely limited (for sensing of conserved pathogen-associated molecular patterns), but evidence exists for both specificity and memory. TCR, T-cell receptor; BCR, B-cell receptor; VLR, variable lymphocyte receptors; V(D)J recombination: randomly combines variable, diverse, and joining gene segments in vertebrate lymphocytes.

Figure 2. First F1 hybrid resistance studies also suggest natural killer (NK)-cell memory and recall responses

In the 1960s, studies demonstrated that parental (A or B) bone marrow or skin grafts given to F1 progeny (A × B) mice were rejected; this observation was called F1 hybrid resistance. In these studies, rejection of a second bone marrow graft occurred more rapidly if the graft was derived from the same parent as the previous graft, suggesting that “pre-treatment” or priming of NK cells results in more potent recall responses during “challenge”. (A) Schematic of experimental design by Gustavo Cudkowicz and Jack Stimpfling published in Nature in 1964. (B) Chart shows results from their experiments. A, B10 mouse strain; B, B10.D2 mouse strain.

Figure 3. Adaptive immune features of natural killer (NK) cells during viral infection

During MCMV infection, the viral ligand m157 is expressed on the surface of infected cells and recognized by Ly49H-expressing NK cells. NK cells receiving Ly49H-mediated signals via DAP12, and IL-12 signals through STAT4, will undergo clonal expansion to generate a large population of effector Ly49H⁺ NK cells. Following a contraction phase that is governed by microRNA-155 and IL-15 signals, self-renewing memory NK cells are long-lived and can mount recall responses against subsequent viral infection.

Figure 4. Priming of adaptive immune characteristics in natural killer (NK) cells by non-pathogenic stimuli

Experimental schematic and observations of immune memory in the NK-cell compartment during priming with chemical haptens (A), exposure to pro-inflammatory cytokines (B), and in settings of lymphopenia (C). (A) NK-cell presence allows for a delayed-type hypersensitivity (DTH) response in mice when repeatedly treated with the same hapten. In mammals, DTH is defined as an hyperinflammatory recall response of the host to an antigen (challenge) that had been exposed earlier to the same antigen (immunization). For years, DTH to haptens (contact hypersensitivity, CHS) has been known as the archetype of adaptive T-cell-mediated immune responses (Vocanson et al, 2009). (B) NK cells memorize cytokine priming event, leading to increased IFN-γ production upon re-exposure to the same inflammatory cytokines as compared to unprimed cells. (C) NK cells are long-lived in lymphopenic mice and expand robustly upon MCMV infection.