How and why do T cells and their derived cytokines affect the injured and healthy brain?

Abstract

The evolution of adaptive immunity provides enhanced defence against specific pathogens, as well as homeostatic immune surveillance of all tissues. Despite being 'immune privileged', the CNS uses the assistance of the immune system in physiological and pathological states. In this Opinion article, we discuss the influence of adaptive immunity on recovery after CNS injury and on cognitive and social brain function. We further extend a hypothesis that the pro-social effects of interferon-regulated genes were initially exploited by pathogens to increase host-host transmission, and that these genes were later recycled by the host to form part of an immune defence programme. In this way, the evolution of adaptive immunity may reflect a host-pathogen 'arms race'.

Figure 1. Immune cells reside in meningeal spaces

The schematic representation shows the three membranes that comprise the meninges: the dura, arachnoid and pia. A full complement of immune cells has been observed in the dura and subarachnoid layers of the meninges and in the cerebrospinal fluid (CSF)^,,–. DC, dendritic cell.

Figure 2. A summary of T cell activity in the injured CNS

Effector T cells (T_eff cells) have diverse effects on outcome following CNS injury; they are capable of promoting either neuroprotection or neurodegeneration. In turn, T_eff cell activity is inhibited by regulatory T cells (T_reg cells), and thus T_reg cells can have either beneficial or detrimental effects on outcome. Several mechanisms of T cell-derived harm (parts a–c) and benefit (parts d–f) have been proposed. a | T cells that acquire either the type 1 T helper (T_H1) or T_H17 phenotypes after CNS injury can secrete cytokines such as interleukin-17 (IL-17), IL-23 and interferon-γ(IFNγ), which have detrimental actions. b | In certain circumstances, T cells can acquire detrimental auto-immune activity, skewing to a T_H1 phenotype and resulting in increased tissue injury. c | T_H1-derived and T_H17-derived cytokines direct local myeloid cells towards a pathological phenotype. Opposite mechanisms have been attributed to beneficial T cells and are typically associated with the T _H2 phenotype. d | Following CNS injury, T cells are activated by a major histocompatibility complex class II (MHC II)-independent, myeloid differentiation primary response protein 88 (MYD88)-dependent signal that promotes T_H2 skew and IL-4 production. IL-4 and brain-derived neurotrophic factor (BDNF), which is produced by CD4⁺ T cells, are directly neuroprotective. e | Certain autoreactive T cells are known to have special neuroprotective qualities. In particular, they more readily accumulate to sites of injury than do other T cells, and they are neuroprotective at these sites. f | T_H2 cells modulate myeloid cells at the injury site, promoting a tissue-healing phenotype. T_H2-derived IL-4 is a promising candidate to mediate macrophage skew, but more work is needed to better understand the molecular mechanisms of these interactions. APC, antigen-presenting cell; TCR, T cell receptor.

Figure 3. IFNγ is necessary for social behaviour

A large proportion of meningeal T cells can produce interferon-γ(IFNγ; which is encoded by Ifng); from the meninges, IFNγ presumably reaches the cerebrospinal fluid (CSF) (dashed arrows). From here, small molecules (<40 kDa) can enter the brain parenchyma through paravascular influx across astrocyte end-feet. IFNγ in the CSF can directly activate layer I inhibitory neurons and boost tonic inhibition of excitatory neurons in the prefrontal cortex (PFC). Mice that lack T cells or IFNγ have aberrant hyperconnectivity (represented by red markings; lower panels) in the PFC and social deficits. Normal social behaviour can be rescued in IFNγ-deficient mice by injecting IFNγ into the CSF or by boosting GABAergic inhibition. AAV, adeno-associated virus; Cre, Cre recombinase; Ifngr1, gene that encodes IFNγ receptor 1; Prkdc, protein kinase, DNA-activated, catalytic polypeptide; Syn, syncytin; Vgat, vesicular GABA transporter; VLA4, very late antigen 4.

Figure 4. Proposed mechanisms for the role of IFNγ in a hypothesized evolutionary ‘arms race’

Signal transducer and activator of transcription (STAT)-induced genes are enriched in primitive social organisms such as Drosophila spp. Viruses (shown in green in this schematic) infect a host and upregulate STAT-dependent transcription of pro-social genes; this promotes aggregation and enhances the spread of the viral genes. Retroviruses can integrate into the host genome, and germline integration of the viral sequences results in vertical transmission and passage of viral DNA. As viral sequences integrated into a host genome can transfer through vertical transmission, these sequences can transmit without inducing sickness behaviour in the host (unlike an acute infection). If transposition results in an upregulation of STAT-dependent transcription of pro-social genes, this could increase the reproductive fitness of the host and further promote increased vertical transmission of viral sequences using natural selection. Further positive selection could arise if transposition of endogenous retroviruses (ERVs) expanded to include target genes for anti-pathogen responses. This would ensure greater immunity (for example, in response to the red virus in the schematic) and increased fitness during times of aggregation and mating. Beyond this, transposition of viral DNA leads to the evolution of adaptive immunity (including the assembly of variable, diversity and joining (VDJ) genes for antigen receptors) and to increased efficiency for defence against pathogens. IFNγ, interferon-γ.