Cytotoxic CD4+ T Cells Drive Multiple Sclerosis Progression

Abstract

Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP (P = 0.003, R2 = 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years (P = 0.005, R2 = 0.29) and with EP and EDSS after 5 years (P = 0.008, R2 = 0.42 and P = 0.003, R2 = 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.

Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization

“…Given that cytolytic granzyme B-producing CD4+CD28- cells are shown to migrate to sites of inflammation in MS where they contribute to tissue damage so that their greater frequency correlates with worse clinical outcome [ 24 , 44 , 68 ], the frequency of granzyme B+ CD4+ T cells infiltrating SC of rats immunized for EAE was examined. Their frequency was considerably higher (p<0.001) in SC of DA rats when compared with their AO counterparts ( Fig 11 ).…”

“…Having all the aforementioned in mind, female Dark Agouti (DA) rats (susceptible to EAE induction) and Albino Oxford (AO) rats (relatively resistant to EAE induction) [ 42 ] were examined for the influence of immunization for EAE on: i) quantitative and qualitative characteristics of thymopoiesis (generation of distinct subpopulation of conventional T cells and CD4+ nTregs), and ii) the phenotypic profile of the main subpopulations of T-peripheral blood lymphocytes (T-PBLs) in terms of the frequency of RTEs, as an indicator of thymopoietic efficacy [ 43 ], and CD28- T cells, as their accumulation, which could also be associated with thymic atrophy, contributes to target tissue damage [ 44 ]. Additionally, to elucidate the putative mechanisms underlying thymopoietic changes, thymic tissue was examined for the expression of molecules regulating thymocyte precursor cell entry into the thymus (CXCL12) [ 45 ], their survival and differentiation/maturation (IL-7, IL-6) [ 46 – 49 ], and differentiation/maturation of CD4+ nTregs (IL-2, IL-15) [ 50 ].…”

A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis

“…We observed an extremely clonal cytotoxic CD4+ T cell population in this sample. Such cells have central roles in autoimmunity 23 , antitumor immunity 24 , 25 , and antiviral defense 26 , 27 . We cannot exclude the possibility that the clone we describe above is restricted by HLA-A2, as both CD4+ T cells restricted by HLA class I and CD8+ T cells restricted by HLA class II have been described in numerous healthy and disease states 28 – 31 .…”

Deciphering targets of Th17 cells fate: From metabolism to nuclear receptors

“…46 Recently, CD4 + CD28were associated with MS progression. 47 Thus, since Th1-like or "ex-Th17" emerged as new potential ectopic sources for GzmB, it seems that they might play an important role in the context of neuroinflammation. Jacquemin et al 48 showed that GzmB induced the formation of reactive oxygen species (ROS) in the mitochondria, independently of the caspase activity and permeabilization of external mitochondrial membrane.…”