Specific elimination of effector memory CD4+ T cells due to enhanced Fas signaling complex formation and association with lipid raft microdomains

Abstract

Elimination of autoreactive CD4þ T cells through the death receptor Fas/CD95 is an important mechanism of immunological selftolerance. Fas deficiency results in systemic autoimmunity, yet does not affect the kinetics of T-cell responses to acute antigen exposure or infection. Here we show that Fas and TCR-induced apoptosis are largely restricted to CD4 þ T cells with an effector memory phenotype (effector memory T cells (T EM )), whereas central memory and activated naïve CD4 þ T cells are relatively resistant to both. Sensitivity of T EM to Fas-induced apoptosis depends on enrichment of Fas in lipid raft microdomains, and is linked to more efficient formation of the Fas death-inducing signaling complex. These results explain how Fas can cull T cells reactive against self-antigens without affecting acute immune responses. This work also identifies Fas-induced apoptosis as a possible immunotherapeutic strategy to eliminate T EM linked to the pathogenesis of a number of autoimmune diseases.

Early in vitro response of macrophages and T lymphocytes to nanocrystalline hydroxyapatites

“…This hyperreactivity is related to the expression of several 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 15 cell surface molecules involved in T cell activation as CD45 RB receptor, abundantly expressed in SR.D10 [18]. The high levels of T cell apoptosis observed in the present study could be explained by the abundant expression of this receptor that favors this death process through Fas and TCR-induced apoptosis [36]. The presence of either nano-HA or nano-SiHA produces a significant increase of SR.D10 apoptosis probably through these mechanisms.…”

“…This hyperreactivity is related to the expression of several cell surface molecules involved in T cell activation as CD45 RB receptor, abundantly expressed in SR.D10 [18]. The high levels of T cell apoptosis observed in the present study could be explained by the abundant expression of this receptor that favors this death process 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 15 through Fas and TCR-induced apoptosis [36]. The presence of either nano-HA or nano-SiHA produces a significant increase of SR.D10 apoptosis probably through these mechanisms.…”

Memory lapses in graft‐versus‐host disease

“…Antigen presentation beyond the initial expansion phase leads to a subsequent failure of rested memory cells to proliferate or produce cytokines upon re-encountering antigen, a defect linked to impaired Jun phosphorylation [25]. Another possibility is that CD4 1 T EM cells could be more prone to Fas-or TCR-mediated apoptosis than other CD4 1 T-cell subsets [26]. While this may be of lesser significance in self-limiting infections, it could be critical under conditions where antigen is present at very high levels [27].…”

Reactivated CD4+Tm Cells of T1D Patients and Siblings Display an Exaggerated Effector Phenotype With Heightened Sensitivity to Activation-Induced Cell Death

“…Alternatively, reactivated CD4 + Tm cells can differentiate into induced regulatory T (iTr) cells, which are important in maintaining self-tolerance through cell surface regulatory receptors and/or inhibitory cytokines (12). After the clearance of a pathogen, a large fraction of CD4 + Tem cells undergo contraction (13). This contraction phase involves activation-induced cell death (AICD).…”

“…Two distinct, but converging pathways mediate AICD in CD4 + Tm cells, including: 1) the extrinsic death receptor pathway (comprising Fas [CD95] or tumor necrosis factor [TNF] receptor 1) and 2) the intrinsic mitochondrial pathway (14). In healthy individuals, Fas-mediated apoptosis has been suggested to play a major role in the elimination of CD4 + Tem cells reactivated by the T-cell receptor (TCR) activation pathway (13).…”