The endogenous repertoire harbors self-reactive CD4+ T cell clones that adopt a follicular helper T cell-like phenotype at steady state

Lee, Victoria; Rodriguez, Donald M; Ganci, Nicole K; Zeng, Sharon; Ai, Junting; Chao, Jaime; Walker, Matthew T.; Miller, Christine H.; Klawon, David E J; Schoenbach, Mary H.; Kennedy, Domenick E.; Maienschein‐Cline, Mark; Socci, Nicholas D.; Clark, Marcus R.; Savage, Peter A.

doi:10.1038/s41590-023-01425-0

Cited by 15 publications

(12 citation statements)

References 69 publications

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“…This bystander activation might provide increased coverage for foreign antigen specificity at the expense of potential cross-reactivity with self (61)(62)(63). Recent identification in mice and humans of autoreactive conventional CD4 + T cells that escape central tolerance and resemble T FH cells (64) suggests that autoreactivity might be an evolutionarily adaptive feature of the follicular T cell repertoire. We observed the presence of an autoreactive follicular T cell clone in the repertoire of control immunized mice, suggesting that mechanisms exist to maintain peripheral tolerance of this potentially autoreactive follicular T cell repertoire.…”

Section: Discussionmentioning

confidence: 99%

T cell help shapes B cell tolerance

Akama-Garren,

Yin,

Prestwood

et al. 2024

Sci. Immunol.

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T cell help is a crucial component of the normal humoral immune response, yet whether it promotes or restrains autoreactive B cell responses remains unclear. Here, we observe that autoreactive germinal centers require T cell help for their formation and persistence. Using retrogenic chimeras transduced with candidate TCRs, we demonstrate that a follicular T cell repertoire restricted to a single autoreactive TCR, but not a foreign antigen–specific TCR, is sufficient to initiate autoreactive germinal centers. Follicular T cell specificity influences the breadth of epitope spreading by regulating wild-type B cell entry into autoreactive germinal centers. These results demonstrate that TCR-dependent T cell help can promote loss of B cell tolerance and that epitope spreading is determined by TCR specificity.

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Section: Discussionmentioning

confidence: 99%

T cell help shapes B cell tolerance

Akama-Garren,

Yin,

Prestwood

et al. 2024

Sci. Immunol.

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“…Visualizations were generated in the R statistical environment (v3.3.1) with the lattice (v0. [24][25][26][27][28][29][30], latticeExtra (v0. and BPG (v5.6.23) packages (61).…”

Section: Data Visualizationsmentioning

confidence: 99%

“…Peripheral self-reactive T cells are present at similar frequencies to T cells specific to foreign antigens ( 24 ) but are held in an anergic state by regulatory T cells (Treg) ( 25 ). However, Treg depletion in healthy mouse models led to the natural occurrence of self-reactive CD4+ T cells ( 26 ). Further, there is mounting evidence for innate-like T-cell populations within mouse and tumor malignancies that have increased propensity for self-reactivity ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

Houlahan

Khan

Greenwald

et al. 2023

Preprint

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Cancer represents a broad spectrum of molecularly and morphologically diverse diseases. Individuals with the same clinical diagnosis can have tumors with drastically different molecular profiles and clinical response to treatment. It remains unclear when these differences arise during disease course and why some tumors are addicted to one oncogenic pathway over another. Somatic genomic aberrations occur within the context of an individual's germline genome, which can vary across millions of polymorphic sites. An open question is whether germline differences influence somatic tumor evolution. Interrogating 3,855 breast cancer lesions, spanning pre-invasive to metastatic disease, we demonstrate that germline variants in highly expressed and amplified genes influence somatic evolution by modulating immunoediting at early stages of tumor development. Specifically, we show that the burden of germline-derived epitopes in recurrently amplified genes selects against somatic gene amplification in breast cancer. For example, individuals with a high burden of germline-derived epitopes in ERBB2, encoding human epidermal growth factor receptor 2 (HER2), are significantly less likely to develop HER2-positive breast cancer compared to other subtypes. The same holds true for recurrent amplicons that define four subgroups of ER-positive breast cancers at high risk of distant relapse. High epitope burden in these recurrently amplified regions is associated with decreased likelihood of developing high risk ER-positive cancer. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an "immune cold" phenotype. These data show the germline genome plays a previously unappreciated role in dictating somatic evolution. Exploiting germline-mediated immunoediting may inform the development of biomarkers that refine risk stratification within breast cancer subtypes.

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“…The production and activation of self‐reactive T cells is an important part in antigen‐specific autoimmune damage. The T cell repertoire of patients with autoimmune diseases harbors self‐reactive CD4+ T cells capable of inducing autoimmunity 7 . Different from HLA haplotype, metabolites and PTM‐related antigen tests, neoantigen‐specific self‐reactive T cell assessment show more about the disease activities.…”

Section: Post‐translationally Modified Neoantigen‐based Disease Activ...mentioning

confidence: 99%

“…The T cell repertoire of patients with autoimmune diseases harbors self-reactive CD4+ T cells capable of inducing autoimmunity. 7 Different from HLA haplotype, metabolites and PTM-related antigen tests, neoantigenspecific self-reactive T cell assessment show more about the disease activities. Experimentally, it is hard to obtain the anti-TCR antibodies, which recognize specific MHCneoantigen complex.…”

Section: Neoantigen-specific Self-reactive T Cell Assessmentmentioning

confidence: 99%