Abstract
Lymphopenic insult has been shown to precipitate the initiation of autoimmune disease in murine models such as the Non-obese diabetic mouse. Similarly, in man lymphopenia induced by mAb therapy, for instance Alemtuzumab as treatment for Multiple Sclerosis, can precipitate development of secondary autoimmune disease in up to 30 % of patients. We asked whether an identified autoimmune susceptibility locus might increase the risk of developing autoimmunity in the context of mAb-induced lymphopenia in a mouse model. A single nucleotide polymorphism (SNP) in the gene encoding the tyrosine phosphatase PTPN22 (R620W) is associated with multiple human autoimmune diseases, and PTPN22 has been shown to modulate T cell responses, particularly to weak antigens. In keeping with this, PTPN22-deficient or PTPN22 R619W mutant murine T cells adoptively transferred into immunodeficient lymphopenic hosts showed a higher lymphopenia-induced proliferation rate than WT cells. We induced lymphopenia by treating wild-type or PTPN22 knock-out mice with T cell depleting antibodies and monitored reconstitution of the T cell pool. We found that PTPN22 deficient T cells acquired a more activated effector phenotype, with significantly more IFNγ producing cells. This resulted from expansion driven by self-peptide MHC, as it was evident when the contribution of IL-7 to lymphopenic expansion was blocked with IL-7R Ab. Interestingly, Foxp3+ Tregs were also considerably expanded in PTPN22-deficient and PTPN22 R619W mice, as was the frequency of both CD25+ and CD25− CD4 T cells that produce IL-10. Using bone marrow chimeric mice, we showed that PTPN22 influenced development of both regulatory and effector T cell functions in a cell-intrinsic manner. Overall the expansion of Tregs is likely to keep the expanded T effector populations in check and sparing Treg during therapeutic mAb depletion may be a useful strategy to prevent occurrence of secondary autoimmunity.
Highlights
Lymphopenia can lead to the expansion of autoreactive T cell clones and may be a risk factor for autoimmune diseases
To test whether Ptpn22 regulated homeostatic T cell proliferation in response to transient lymphopenia in mice we chose an Abmediated lymphopenia model, as this was similar to the mode of action of drugs such as Alemtuzumab which is used for lymphodepletion therapy in man
Using anti-CD4 and anti-CD8 antibodies in combination we found that severe T cell depletion was followed by transient proliferation and activation of T cells until T cell homeostasis was restored
Summary
Lymphopenia can lead to the expansion of autoreactive T cell clones and may be a risk factor for autoimmune diseases. The risk of developing secondary autoimmunity following lympho-depletion regimes might be increased for Abbreviations: Ab, antibody; IFN, interferon; IL, interleukin; KO, knock-out; LIP, lymphopenia induced proliferation; mAb, monoclonal antibody; MHC, major histocompatibility complex; p, peptide; p. I., post injection; PTPN, protein tyrosine phosphatase non-receptor; SNP, single nucleotide polymorphism; TCR, T cell receptor; Treg, regulatory T cell These patients given that they started with an underlying autoimmune disease and may have increased predisposition to self-reactivity. In keeping with clinical human lymphodepletion regimes, we induced severe lymphopenia by treating mice with monoclonal anti-CD4 and anti-CD8 depleting antibodies and monitored the reconstitution of the T cell pool In this model upon reconstitution, PTPN22 deficient T cells acquired an enhanced activated effector phenotype, with significantly higher production of IFNγ compared to wildtype T cells. Our data indicate that maintaining a high Treg:T effector cell ratio in mAb depletion therapies may be beneficial in preventing secondary autoimmunity
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