PT  - JOURNAL ARTICLE
AU  - Timothy W. Houston
AU  - Quentin Howlett-Prieto
AU  - Colin Regenauer
AU  - Fernando D. Testai
AU  - Faith Yao
AU  - Xuan Feng
AU  - Anthony T. Reder
TI  - Increased Percentage of CD8<sup>+</sup>CD28<sup>−</sup> Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
AID  - 10.1212/NXI.0000000000200075
DP  - 2023 Mar 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e200075
VI  - 10
IP  - 2
4099  - http://nn.neurology.org/content/10/2/e200075.short
4100  - http://nn.neurology.org/content/10/2/e200075.full
SO  - Neurol Neuroimmunol Neuroinflamm2023 Mar 01; 10
AB  - Background and Objectives Fingolimod, an oral therapy for MS, decreases expression of membrane S1P1 receptors on CD4+ memory cells, causing their retention and deactivation in lymph nodes. We determined fingolimod effects on the number and proportion of potentially CNS-damaging CD8+CD28+ cytolytic T lymphocyte cells (CTLs) and on MS-depleted and dysfunctional CD8+CD28− anti-inflammatory suppressor/regulatory T cells (Treg) and on CD8+ T-cell expression of the CD69 activation/lymph node retention protein in MS.Methods CD8, CD28, CD4, and CD69 expression on peripheral blood mononuclear cells was measured with flow cytometry. In vitro concanavalin A (ConA) activation of T cells, including CD8+CD28− cells, was used to mimic inflammation.Results Fifty-nine patients with MS, 35 therapy-naive (16 clinically stable; 19 exacerbating) and 24 fingolimod-treated (19 clinically stable; 5 exacerbating), and 26 matched healthy controls (HCs) were compared. In therapy-naive patients, the CD8+ Treg percent of total lymphocytes was only 1/4 of HC levels. In fingolimod-treated patients, however, CD8+ Treg percentages rose to 2.5-fold higher than in HC and 10-fold higher than in therapy-naive MS. With fingolimod therapy, in contrast, CD8+ CTL levels were less than half of levels in HCs and therapy-naive patients. In HCs and all MS, activation with ConA strongly induced CD69 expression on CD4+ cells and induced 3-fold higher CD69 levels on CD8+ CTL than on CD8+ Treg. Fingolimod and analogs in vitro did not modify lymphocyte CD69 expression. Lower levels of CD69 on CD8+ Treg than on CTL may allow easier Treg egress from lymph nodes and enhance control of peripheral inflammation. In vitro activation reduced the already low CD8+ Treg population in therapy-naive MS, but only slightly altered Treg levels in fingolimod-treated MS.Discussion Fingolimod therapy markedly increases the percentage of CD8+ Treg in MS, reversing the low CD8+ Treg:CTL ratio seen in untreated MS. The increase in immune regulatory cells has potential therapeutic benefit in MS. Activation in vitro depletes CD8+CD28+CTL in patients with MS; the loss is more pronounced in older patients with MS. This suggests that inflammation can disrupt the tenuous immune regulation in MS, especially in older patients.B=Black/African ancestry; ConA=Concanavalin A mitogen; CTL=Cytolytic T lymphocyte; DNS=Data not shown; EDSS=Extended disability scale score of Kurtzke; F=Female; FTY=Fingolimod/FTY720; FTY-p=FTY-phosphate; H=Hispanic; HC=healthy control; I=Indian/South Asian; M=Male; MFI=Median fluorescence intensity; MS-a=Active/exacerbating MS; MS-s=Clinically stable MS; N=Number; NA=Not applicable; NS=Not significant; O=Other (East Asian ancestry); PBMC=Peripheral blood mononuclear cell; PPMS=Progressive forms of MS; RRMS=Stable relapsing/remitting MS; Rx=Treatment; S1PR=Sphingosine 1-phosphate receptor; SEM=Standard error of the mean; SPMS=Secondary Progressive form of MS; Treg=Regulatory T cell; W=White/Caucasian