Page 43 - Power of Stem Cells- arthritis and regeneration

Luque-Campos et al. MSCs and Memory T Cells in RA

following antigen exposure that provides lifelong protection Role of Memory T Cells in the Development
against infections (30). and Progression of RA
Memory T cells are an heterogeneous population of RA is an autoimmune disease characterized by the high
cells classically distinguished by the expression of the production of auto-antibodies affecting a wide variety of auto-
CD45RO isoform and by the absence of the CD45RA antigens. Among them, the rheumatoid factor (RF) and anti-
+
(CD45RO CD45RA ) (31, 32). Lately, in human, specific citrullinated protein antibodies (ACPAs) have been the most
−
subsets of memory CD4 + and CD8 + T cells in peripheral described (47). RA immunopathogenesis is characterized by
blood mononuclear cells (PBMCs) were identified through the deficiencies in the immune response with predominance of pro-
expression of CC-chemokine receptor 7 (CCR7), a chemokine inflammatory cells and an alteration of the peripheral immune
receptor that controls the homing to secondary lymphoid tolerance which involves in particular CD4 + T cells (48, 49).
organs (33). CCR7 negative memory T cells were found to CD4 + T cells of RA patients undergo a premature transition
produce more effector cytokines, compared to the CCR7 positive from a naïve to a memory phenotype. The resulting memory
subset (34). Based on this finding, two subsets of memory T CD4 + T cells are hyper-proliferative because of failures in
cells were identified: CCR7 + central memory T cells (T CM ) the cell cycle checkpoint which promote their differentiation
and CCR7 − effector memory T cells (T EM ) (33). Several toward Th1 and Th17 pathogenic T cells (50). This was
studies have been carried out to characterize the memory cells confirmed in studies demonstrating that RA patients have large
present in PBMC using an extensive panel of markers. The numbers of memory CD4 T cells that infiltrate the inflamed
hi
hi
hi
hi
CD44 , CD45RO , CD45RA low , CD127 , CD62L CCR7 hi synovial membrane (51–55). Moreover, the increased frequency
T CM cells are generated and reside in secondary lymphoid of T EM cell subset was observed in the synovial fluid from
hi
hi
tissues in the absence of antigen while CD44 , CD45RO , RA patients (55). While T EM cells have a short lifetime they
hi
CD45RA low , CD127 , L-selectin low CCR7 low T EM cells, are possess a potent effector function with a high capacity to secrete
generated in secondary lymphoid tissues and recirculate pro-inflammatory cytokines allowing them to respond faster
between blood and non-lymphoid tissues in the absence of to antigens present in the synovial fluid (34). All together,
antigen (33). these studies suggest the presence of highly activated and
As mentioned before, the long-lived memory T cells in differentiated memory CD4 + T cells with a high capacity
the presence of secondary antigen exposure expand and to produce pro-inflammatory cytokines in synovial fluid of
develop a more robust and stronger response. In the case RA patients.
of autoimmune diseases memory T cells might become
harmful against self-antigens since these memory cells
exhibit a potent pathogenic response against self-tissues. Conventional Therapy for RA Treatment
Moreover, due to their longevity, they are very difficult A large variety of drugs aiming at reducing the symptoms
to eliminate thus the development of novel therapies and gradual progression of the disease are currently available.
directed against these cells are of main importance to Among them, synthetic disease-modifying anti-rheumatic drugs
control autoimmunity. (sDMARDs) including methotrexate (MTX), leflunomide,
In this context, the role of memory T cells in autoimmune sulfasalazine, and hydroxychloroquine, biologic response
diseases has been studied. MS patients have an elevated numbers modifiers referred as biologics (bDMARDs) and corticosteroids.
of memory T cells (35–37), particularly of the T EM subsets (38, All these treatments target inflammation and are aimed at
39). Recently it has been reported that memory CD4 CCR9 + improving both the quality of life and prognosis of RA patients
+
T cells are altered in MS patients and they could be mediate (56) through the prevention of structural damage (erosive
the development of secondary progressive MS progression (40). disease) and control of extra-articular symptoms. Since, RA
Also, it has been reported that memory T cells subpopulation pathogenesis is associated to alterations of immune cell functions
are increased in active Crohn’s disease patients (41, 42). Indeed, and cytokine secretion produced in part by pro-inflammatory
peripheral blood and intestinal mucosa memory T cells from CD4 T memory responder cells, a wide variety of bDMARDs
+
active Crohn’s disease patient have an increased intracellular have been proposed to target the latter cells. For instance, the
production of TNFα and correlate with the score of the disease first bDMARD tested was aimed at reducing the production
(CDAI). In addition, this peripheral blood memory T cells- of tumor necrosis factor alpha (TNF-α) (Infliximab), a pro-
producing TNFα have an increased migratory profile to extra inflammatory cytokine highly produced by memory T cells of
nodal lymphoid tissues such as the intestinal mucosa (43). RA patients (57). Since then, other TNF-targeting agents such
Furthermore, there is evidence suggesting an augmentation of as etanercept, adalimumab, certolizumab, and golimumab as
CD4 + T EM cells population in SLE pathogenesis (44). Also, well as other biological agents such as anti-IL6 (tocilizumab),
+
+
the PD1 ICOS T CM , and PD1 ICOS T EM subpopulation are anti-CTLA4 (abatacept), and anti-CD20 (Rituximab) were
+
+
increased in SLE patients and T EM positively cells correlated developed (56). However, the treatment of some RA patients
with the severity of the disease (45). Likewise, it has been with TNF inhibitors did not significantly reduce the frequency
observed an enrichment of CD4 + T EM -cell associated genes of pathogenic Th17 cells revealing that a high range of patients
within SLE loci, Crohn’s loci and RA loci (46). All this do not respond to this treatment (57). Later, an anti-interleukin
evidence point memory T cell subsets as major contributors of 17 (IL-17) antibody (secukinumab) and anti-IL-17RA antibody
autoimmune pathogenicity. brodalumab (AMG827) were developed and evaluated in

Frontiers in Immunology | www.frontiersin.org 3 April 2019 | Volume 10 | Article 798