Follicular helper T cells: implications in neoplastic hematopathology

Abstract

A distinct subset of T helper cells, named follicular T helper cells (T(FH), has been recently described. T(FH) cells are characterized by their homing capacities in the germinal centers of B-cell follicles where they interact with B cells, supporting B-cell survival and antibody responses. T(FH) cells can be identified by the expression of several markers including the chemokine CXCL13, the costimulatory molecules PD1 and inducible costimulator, and the transcription factor BCL6. They appear to be relevant markers for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and have helped to recognize subsets of peripheral T-cell lymphoma, not otherwise specified, with nodal or cutaneous presentation expressing T(FH) antigens that might be related to AITL. In B-cell neoplasms, T(FH) cells are present within the microenvironment of nodular lymphocyte-predominant Hodgkin lymphoma and follicular lymphoma, where they likely support the growth of neoplastic germinal center-derived B cells. Interestingly, the amount of PD1+ cells in the neoplastic follicles might have a favorable impact on the outcome of follicular lymphoma patients. Altogether, the availability of antibodies directed to T(FH)-associated molecules has important diagnostic and prognostic implications in hematopathology. In addition, T(FH) cells could represent interesting targets in T(FH)-derived lymphomas such as AITL, or in some B-cell neoplasms where they act as part of the tumor microenvironment.

Figure 1. Follicular helper T cells

Follicular helper T cells and derived lymphomas. Follicular helper T cells normally present in the light zone of reactive germinal center (upper left panel, immunostaining with anti-CD57) have been demonstrated as the cell of origin of several lymphoma entities (upper right panel, for details see text). The main distinctive immunophenotypic features of TFH cells are summarized in the lower panel table. Abbreviations: CXCR5: Chemochine (C-X-C motif) receptor 5 CXCL13: Chemokine (C-X-C motif) ligand 13 (B-cell chemoattractant) ICOS: Inducible T-cell Co-Stimulator (ICOS) protein SAP: SLAM-associated protein (SH2D1A)

Figure 2. Angioimmunoblastic T-cell lymphoma

(A) Low power magnification of a case characterized by a mixed pattern, comprising large reactive follicles with an attenuated mantle zone, and a diffuse proliferation in association with increased vascularisation ; (B) High power view showing prominent vascularisation, and a mixed infiltrate comprising large blastic cells, eosinophils, and an infiltrate of small to medium atypical lymphoid cells ; (C) CD21 highlights a follicular dendritic cell meshwork, in association with follicles, (F) and outside the follicles ; (D) CD20 stains large blastic cells outside the follicles (F) ; (E–H) the neoplastic cells are positive for several T_FH markers including PD1 (E), CXCL13 (F), BCL6 (G) and c-MAF (H).

Figure 2. Angioimmunoblastic T-cell lymphoma

(A) Low power magnification of a case characterized by a mixed pattern, comprising large reactive follicles with an attenuated mantle zone, and a diffuse proliferation in association with increased vascularisation ; (B) High power view showing prominent vascularisation, and a mixed infiltrate comprising large blastic cells, eosinophils, and an infiltrate of small to medium atypical lymphoid cells ; (C) CD21 highlights a follicular dendritic cell meshwork, in association with follicles, (F) and outside the follicles ; (D) CD20 stains large blastic cells outside the follicles (F) ; (E–H) the neoplastic cells are positive for several T_FH markers including PD1 (E), CXCL13 (F), BCL6 (G) and c-MAF (H).

Figure 3. Follicular peripheral T-cell lymphoma

(A) At low magnification there is a vaguely nodular pattern reminiscent of progressively transformed germinal centres, and scattered paler aggregates ; (B) the aggregates of pale cells representing the neoplastic population consist of atypical medium-sized lymphocytes with moderately abundant clear cytoplasm; mitotic figures are seen ; (C) the neoplastic cells which are CD3+ CD4+ (not shown) have strong membrane expression of PD1 ; (D) cytoplasmic granular positivity for CXCL13 ; (E) express CD10 ; and (F) show nuclear positivity for BCL6.

Figure 4. Primary cutaneous small/medium-sized CD4+ T-cell lymphoma

(A)This lymphoma which presented as an isolated lesion of the eyelid in a 55 y-old man, consisted of a dense and diffuse lymphoid infiltrate occupying the the upper and mid-dermis ; (B) it was composed of small to medium sized slightly atypical lymphoid cells, with scattered histiocytes and larger cells ; (C and inset) the lymphoid cells had a CD2+ CD3+ CD4+ immunophenotype (not shown) with strong coexpression of PD1 in the majority of the cells.

Figure 5. PD1 expression in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)

The classic nodular pattern (A–C) and the diffuse pattern (D–F) of NLPHL are illustrated. PD1 immunostaining is helpful to decorate rosettes of T cells around neoplastic LP cells in both nodular (E) and diffuse (F) areas.