The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Abstract

The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Rα+ CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Rα+CD8+ and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8+IL-7Rα+ in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα+ lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

“…Previously, we showed that no correlation exist between levels of membrane IL-7Ra expression and the rs6897932 [C] MS risk genotype. 16 Hence, only the levels of the soluble IL-7Ra correlate with the risk genotype (Figure 1b). It is conceivable that the lower serum concentrations of 'unbound' IL-7 and 'free' sIL-7Ra, in conjunction with the increased membrane-bound IL-7Ra found in MS patients, lead to an increased IL-7 responsiveness when IL-7 binds to the membrane-bound receptor.…”

“…Comparable conclusions were drawn by Rose et al 14 Membrane expression of the IL-7Ra on most CD8 T-cell subsets is significantly increased in MS patients and the frequency of IL-7Ra þ CD8 effector memory subset (CD8EM defined as CD27 À CD45RA À ) is significantly higher in MS patients. 16 Therefore, we investigated whether systemic concentrations of sIL-7Ra correlate with the level of IL-7Ra membrane expression on functional CD4 and CD8 lymphocyte subsets. We found that in 52 MS patients compared with 44 HCs the ratio between mean fluorescence intensity (an estimate for the number of receptors per cell) of IL-7Ra on both CD4 and CD8 T cells and the sIL-7Ra levels is significantly increased (Figures 4a and b, Po0.01.…”

“…17 Increased IL-7Ra signaling capacities were observed in CD8 T cells of MS patients, leading to increased mRNA expression of cytotoxic molecules. 16 Moreover, altered expression of both the membrane and soluble form potentially provides a survival advantage, as membranebound IL-7Ra signaling prevents activation induced cell death. 18 Reactive astrocytes in MS white matter brain lesions produce IL-7, 19 suggesting that the potential increased IL-7 responsiveness of CD8 T cells leads to enhanced cytotoxic responses in the brain, potentially inducing tissue damage.…”

Interleukin‐12 (IL‐12), but not IL‐23, induces the expression of IL‐7 in microglia and macrophages: implications for multiple sclerosis

“…Granzyme A particularly is capable of causing direct myelin damage via degradation of myelin basic protein (MBP). 17,19 Interleukin-12 plays a critical role in the early inflammatory response to infection and in the generation of Th1 cells, which favour cell-mediated immunity. 20 It has been found that over-production of IL-12 can be dangerous to the host because it is involved in the pathogenesis of a number of autoimmune inflammatory diseases (e.g.…”

“…The frequency of CD127 + CD8 effector memory T cells and the expression levels of CD127 on most CD8 + subsets increase in MS patients. 17 In the case of MS, they potentially migrate into the central nervous system (CNS), where they re-encounter IL-7 produced by reactive microglia and astrocytes. 17,18 This intrathecally produced IL-7 may further activate and increase the cytoxic potential of these T cells by the up-regulation of genes involved in cytoxicity such as granzymes A and B, and induction of a E b 7 integrin.…”