Identical twins discordant for multiple sclerosis have a shift in their T-cell receptor repertoires

Abstract

CD4 T-cells have an important role in the autoimmune response in multiple sclerosis (MS). We investigate the possibility that a shift occurs in the T-cell receptor (TR) repertoire of identical twins discordant for MS. We compare the CDR3 spectratype distributions of 24 different TR V beta (TRBV) segments in naïve CD4 T-cells from discordant MS twins and from healthy identical twins. We also compare the CDR3 spectratype distributions in unrelated healthy pairs, formed by combining members of different healthy twins, with the CDR3 spectratype distributions in unrelated pairs of MS patients and in unrelated pairs of their apparently healthy cotwins, formed by combining members of different discordant twins. We use the correlation coefficient (r-value) as a measure of similarity of CDR3 spectratypes in each pair, and we test for the significance of the difference between r-values from the different pairs. We observe that the r-value for the CDR3 spectratype distributions among discordant twins differs significantly from the corresponding r-value for the healthy twins for two TRBV segments. Further, the r-values, for both the unrelated MS patient pairs and the unrelated pairs of their apparently healthy cotwins, differ significantly from the r-values for healthy unrelated pairs of individuals. We conclude that both the MS patients and their apparently healthy cotwins have shifts in their CDR3 repertoires. Because we study naïve CD4 T-cells, we postulate that CDR3 repertoire shifts precede MS and predispose to MS, but are unlikely to be sufficient to cause MS.

Fig. 1

TRBV20-1 CDR3 spectratype distributions of naïve CD4 T-cells from (a) four healthy identical twin pairs (the r-value for each twin pair varied between 0·982 and 0·998) and (b) four discordant MS twin pairs (the r-value for each twin pair varied between 0·972 and 0·997).

Fig. 1

TRBV20-1 CDR3 spectratype distributions of naïve CD4 T-cells from (a) four healthy identical twin pairs (the r-value for each twin pair varied between 0·982 and 0·998) and (b) four discordant MS twin pairs (the r-value for each twin pair varied between 0·972 and 0·997).

Fig. 2

TRBV5-5 CDR3 spectratype distributions of naïve CD4 T-cells from (a) four healthy identical twin pairs (the r-value for each twin pair varied between 0·947 and 0·995) and (b) four discordant MS twin pairs (the r-value for each twin pair varied from 0·882 to 0·993).

Fig. 2

TRBV5-5 CDR3 spectratype distributions of naïve CD4 T-cells from (a) four healthy identical twin pairs (the r-value for each twin pair varied between 0·947 and 0·995) and (b) four discordant MS twin pairs (the r-value for each twin pair varied from 0·882 to 0·993).

Fig. 3

TRBV7-8 CDR3 spectratype distributions of naïve CD4 T-cells from (a) three healthy identical twin pairs (the r-value for each twin pair was 0·997) and (b) four discordant MS twin pairs (the r-value for each twin pair varied from 0·975 to 0·979). (c) Image of sequencing gel of duplicate PCR amplifications and TRBV7-8 spectratypes from two discordant twins run in parallel. Lanes 1–4 show the duplicate CDR3 spectratypes from each member of one discordant pair, and lanes 5–8 show duplicate CDR3 spectratypes from each member of a second discordant pair.

Fig. 3

TRBV7-8 CDR3 spectratype distributions of naïve CD4 T-cells from (a) three healthy identical twin pairs (the r-value for each twin pair was 0·997) and (b) four discordant MS twin pairs (the r-value for each twin pair varied from 0·975 to 0·979). (c) Image of sequencing gel of duplicate PCR amplifications and TRBV7-8 spectratypes from two discordant twins run in parallel. Lanes 1–4 show the duplicate CDR3 spectratypes from each member of one discordant pair, and lanes 5–8 show duplicate CDR3 spectratypes from each member of a second discordant pair.

Fig. 3

TRBV7-8 CDR3 spectratype distributions of naïve CD4 T-cells from (a) three healthy identical twin pairs (the r-value for each twin pair was 0·997) and (b) four discordant MS twin pairs (the r-value for each twin pair varied from 0·975 to 0·979). (c) Image of sequencing gel of duplicate PCR amplifications and TRBV7-8 spectratypes from two discordant twins run in parallel. Lanes 1–4 show the duplicate CDR3 spectratypes from each member of one discordant pair, and lanes 5–8 show duplicate CDR3 spectratypes from each member of a second discordant pair.