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Fc receptor Signaling from Immune Complexes Drives Th1 Expansion

Submitter: Anil Chauhan | chauhanakc0@gmail.com

Authors: Anil Chauhan

Saint Louis University

Published July 10, 2020

The recently published article by Rasoulouniriana et. al, demonstrate that the FcgR1 expressing CD4⁺ Th1 subset exert antibody-mediated cytotoxic activity, report an important FcR mediated function. (1). The role of Fc receptors (FcRs) in CD4⁺ T cell function remains controversial (2-4). Authors suggested that the Th1 population only express FcgRI, though their flow analysis also show FcgRII/FcgRIII (Fig. 3A). Indeed, Th1 population can be generated from ICs ligation to CD16a on human naïve CD4⁺ T cells (5). It would have been nice to identify, which of three FcR⁺ populations produce IFN-g. There is no existing experimental data that support the absence of FcR expression from CD4⁺ T cells (3). Many groups, including ours have established the existence of FcRs on activated CD4⁺ T cells (2, 4, 5). FcR signaling drives the differentiation of human naïve CD4⁺ T cells into IFN-g producing T-bet⁺ Th1 cells (5-7). However, as implied in the article, we did not show that IFN-g exposure triggered FcR expression or cellular activation. FcgRIIIa activation by ICs is required for type I and II IFN expression (7). Signaling from FcgRIIa and FcmR1 also trigger IFN-g production (9, 10). We disagree that the Th1 cells observed are exhausted. The levels of expression of TIM3, LAG3, and PD1 stained in FcgRI⁺ cells upon PMA + Ionomycin is not convincing and these markers should have been examined in anti-CD3 +anti-CD28 treated cells. Authors showed Syk, which would suggest an activated state, and to make a case for exhausted state, should have performed co-staining. The FcgRIIa and FcgRIIIa signaling shows pSyk in cells, which express CD25, CD69, and CD98, suggesting cellular activation (7, 11).

 

Requirement of TRP-1 and anti-TRP-I to kill tumor cells, suggests type II hypercreativity reaction. Authors suggested that combined TRP1-reactive TCR, FcgRI, and FcRg T cells and anti-TRP1 antibodies induced tumor eradication. FcRs that bind to ICs are present on the activated CD4⁺ T cell membranes with CD3 complex in clustered membrane rafts (12).

 

The authors suggested that IFN-g triggered lysosome production that resulted in cell death. FcR signaling upregulates the granzymes. We observed enhanced expression of Gran A from FcR signaling. Forced expression of FcRg enhances the ADCC and CD16a expression (13, 14). The modest PD1⁺ population produces IFN-g (6). We are of the opinion that the FcR expressing cells do not represent exhausted cells as suggested in this study. Other interpretation of their result is also possible. 

 

 

                                         

 

1.         Rasoulouniriana D, Santana-Magal N, Gutwillig A, Farhat-Younis L, Wine Y, Saperia C, et al. A distinct subset of FcgammaRI-expressing Th1 cells exert antibody-mediated cytotoxic activity. The Journal of clinical investigation. 2019;129(10):4151-64.

2.         Chauhan AK. Human CD4+ T-cells-A Role for low affinity Fc-receptors. Front Immunol. 2016;10.3389/fimmu.2016.00215( ).

3.         Nimmerjahn F, and Ravetch JV. Fcgamma receptors as regulators of immune responses. Nature reviews Immunology. 2008;8(1):34-47.

4.         Sandor M, and Lynch RG. Lymphocyte Fc receptors: the special case of T cells. Immunology today. 1993;14(5):227-31.

5.         Chauhan AK, Chen C, Moore TL, and DiPaolo RJ. Induced Expression of FcgammaRIIIa (CD16a) on CD4+ T Cells Triggers Generation of IFN-gammahigh Subset. The Journal of biological chemistry. 2015;290(8):5127-40.

6.         Chauhan AK. Immune Complex (ICs) generate PD1int CD4+ T cells which are Bcl6+IFN-γ+ unlike exhausted PD1high cells. J Immunology. 2019;202 (1 supplement)(188):13.

7.         Chauhan AK, Moore TL, Bi Y, and Chen C. FcgammaRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression. The Journal of biological chemistry. 2016;291(3):1368-86.

8.         Chauhan AK. FcgammaRIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells. J Immunol. 2017;198(12):4596-606.

9.         Holgado MP, Sananez I, Raiden S, Geffner JR, and Arruvito L. CD32 Ligation Promotes the Activation of CD4(+) T Cells. Front Immunol. 2018;9:2814.

10.       Meryk A, Pangrazzi L, Hagen M, Hatzmann F, Jenewein B, Jakic B, et al. Fcmu receptor as a Costimulatory Molecule for T Cells. Cell Rep. 2019;26(10):2681-91 e5.

11.       Chauhan AK, and Moore TL. Immune complexes and late complement proteins trigger activation of Syk tyrosine kinase in human CD4(+) T cells. Clinical and experimental immunology. 2012;167(2):235-45.

12.       Chauhan AK, and Moore TL. T cell activation by terminal complex of complement and immune complexes. The Journal of biological chemistry. 2011;286(44):38627-37.

13.       Clemenceau B, Vivien R, Berthome M, Robillard N, Garand R, Gallot G, et al. Effector memory alphabeta T lymphocytes can express FcgammaRIIIa and mediate antibody-dependent cellular cytotoxicity. J Immunol. 2008;180(8):5327-34.

14.       O’llier J, Vivien R, Vie H, and Clémenceau B. Transfection of FcgRIIIa (CD16) alone can ee sufficient to enable human abTCR T lymphocytes to mediate antibody-dependent cellular cytotoxicity. ImmunoHorizon. 2017;1(5):63-70.