Follicular HELPer T cells HELPing us Predict Clinical Response to Immunotherapy

Follicular HELPer T cells HELPing us Predict Clinical Response to Immunotherapy

By: Neha Majety

T cells? Sure we’ve heard of them. Follicular helper T (TFH) cells? Maybe not. 

What are TFH cells? What do they do? 

TFH cells are a subset of CD4+ T helpers, and they play an important role in the generation of antibodies and the formation of germinal centers, as well as the development of memory B cells. They have been linked to T1D and CD28 stimulation. 

Why are they Important to T1D and Autoimmune Conditions in General? 

According to a 2019 article, TFH cells might further trigger beta cell destruction because they can cause an overgeneration of autoantibodies linked to T1D. This article reviewed TFH cell’s role in autoimmunity and found:

  • Regular functioning TFH cells are crucial for development of protective immunity.
  • Abnormally high levels of autoantigens trigger an overwhelming induction of TFH cells,  resulting in production of autoantibodies. 
  • TFH cell associated genes (CXCR5, IL-21, PDCD1 and Bcl-6) are upregulated in islet-specific T cells of murine pancreatic lymph nodes. 

Overall, this data suggests that TFH cells can act as a potential biomarker and give way to new therapeutic strategies.

Speaking of Therapeutic Strategies, What is Abatacept? 

Abatacept is an immunotherapy drug used to cause a costimulation blockade in individuals with certain autoimmune diseases, including T1D and Rheumatoid Arthritis. To cause the costimulation blockade, Abatacept uses CTLA-4, which is a natural regulator of CD28, a molecule that marks T cells for activation and is linked to T1D.

TFH Cells, a Potential Stratification Tool?

Researchers in London examined differing TFH profile responses to the costimulation blockade caused by Abatacept to create a model that predicted clinical response to the drug. Their study was the first to find baseline TFH phenotypes as a potential predictor for clinical response to immunotherapies. Their major findings included: 

  • Inducible costimulatory molecule (ICOS) populations, including ICOS+ T cells, were extremely sensitive to costimulation blockade. 
    • One such sensitive population was Peripheral T helper (TPH) cells that are expanded in children with islet autoantibodies who go on to develop T1D.
  • Post-Abatacept treatment, TFH cells exhibited altered phenotype with a decrease in ICOS+ TFH cell populations and an increase in ICOS-PD-1- TFH cells.
    • Continuous requirement of CD28 signaling is needed to sustain ICOS expressions, and ICOS expression is crucial for normal TFH characteristics.
  • Data suggested that the costimulation blockade primarily inhibits early TFH cell differentiation, but if prolonged, can effectively inhibit ICOS signaling altogether – making all TFH cells ICOS-. 

The model found that those with higher frequencies of ICOS+ TFH cells were associated with poor clinical response, while those with higher frequencies of ICOS and PD-1 double negative TFH cells were associated with better clinical responses. Thus, it can be concluded that ICOS could be an important marker associated with preservation of beta cell function (post-Abatacept treatment).

Look Forward:

Further research can be conducted to determine whether T cell phenotypes can predict response to Abatacept for other autoimmune diseases or response to other immunotherapies in general. 

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